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Copenhagen, Denmark

The University of Copenhagen is the oldest university and research institution in Denmark. Founded in 1479 as a studium generale, it is the second oldest institution for higher education in Scandinavia after Uppsala University . The university has 23,473 undergraduate students, 17,398 postgraduate students, 2,968 doctoral students and more than 9,000 employees. The university has four campuses located in and around Copenhagen, with the headquarters located in central Copenhagen. Most courses are taught in Danish; however, many courses are also offered in English and a few in German. The university has several thousands of foreign students, of whom about half come from Nordic countries.The university is a member of the prestigious International Alliance of Research Universities , along with University of Cambridge, University of Oxford, Yale University, The Australian National University, and UC Berkeley, amongst others. The Academic Ranking of World Universities, compiled by Shanghai Jiao Tong University, saw the University of Copenhagen as the leading university in Scandinavia and ranked 39th best university in the world in 2014. It is ranked 45th in the 2014 QS World University Rankings and 13th in Europe. Moreover, in 2013, according to the University Ranking by Academic Performance, the University of Copenhagen is the best university in Denmark and the 25th university in the world. The university has had 8 alumni become Nobel laureates and has produced one Turing Award recipient. Wikipedia.


Ancient DNA extracts consist of a mixture of endogenous molecules and contaminant DNA templates, often originating from environmental microbes. These two populations of templates exhibit different chemical characteristics, with the former showing depurination and cytosine deamination by-products, resulting from post-mortem DNA damage. Such chemical modifications can interfere with the molecular tools used for building second-generation DNA libraries, and limit our ability to fully characterize the true complexity of ancient DNA extracts. In this study, we first use fresh DNA extracts to demonstrate that library preparation based on adapter ligation at AT-overhangs are biased against DNA templates starting with thymine residues, contrarily to blunt-end adapter ligation. We observe the same bias on fresh DNA extracts sheared on Bioruptor, Covaris and nebulizers. This contradicts previous reports suggesting that this bias could originate from the methods used for shearing DNA. This also suggests that AT-overhang adapter ligation efficiency is affected in a sequence-dependent manner and results in an uneven representation of different genomic contexts. We then show how this bias could affect the base composition of ancient DNA libraries prepared following AT-overhang ligation, mainly by limiting the ability to ligate DNA templates starting with thymines and therefore deaminated cytosines. This results in particular nucleotide misincorporation damage patterns, deviating from the signature generally expected for authenticating ancient sequence data. Consequently, we show that models adequate for estimating post-mortem DNA damage levels must be robust to the molecular tools used for building ancient DNA libraries.


Hastrup K.,Copenhagen University
Wiley Interdisciplinary Reviews: Climate Change | Year: 2013

In the world of climate science there is an increasing demand for contributions from the social sciences, given that the current processes of climate change deeply affect societies. This article is a response to this call, with specific focus on past and potential contributions from anthropology, as we have known it from the 19th century onwards. It is shown how through the ages, different anthropological interests have shaped distinct perspectives on the entanglement of society and nature. It is argued that the present global concerns about climate change necessitate a refashioning of anthropology, and make it expedient to pay attention to the emergent global imaginaries. WIREs Clim Change 2013, 4:269-281. doi: 10.1002/wcc.219 Conflict of interest: The author has declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. © 2013 John Wiley & Sons, Ltd.


Hansen S.,Copenhagen University
Journal of Applied Crystallography | Year: 2013

A new method for approximation of the structure factor for nonspherical hard bodies is suggested. It is shown that for moderate deviation from spherical symmetry the structure factor may be approximated by the structure factor for a size distribution of spheres. The distribution of spheres should be selected to give agreement between the excluded volume distance distribution functions for the two cases. As the excluded volume distance distribution may be calculated by Monte Carlo simulation for any particle and as a semi-analytical expression exists for the excluded volume distance distribution of a size distribution of spheres, it should be possible to apply the method to any shape of molecule. For ellipsoids of axial ratios between 0.5 and 2.0 a simple approximate expression is given for the parameters of the matching size distribution. © 2013 International Union of Crystallography Printed in Singapore - all rights reserved.


Jorgensen S.E.,Copenhagen University
Ecological Complexity | Year: 2010

It is proposed to calculate the value of ecosystem services by the annual increase of work capacity or eco-exergy. The annual increase of biomass for various ecosystems is known. By multiplication of the biomass increase by the average content of information as Kullbach's measure of information, in the various ecosystems, the eco-exergy or total work capacity is obtained. An economic value can be found by multiplication of the cost of work, which is about 1 EURO-cent per MJ. A comparison of this value with the values found by Costanza et al. (1997) shows that the value based upon the total work capacity is much higher. The ratio between the two economic values have been found for the various ecosystems. It has been found that the ratio is lower the more an ecosystem by a wide range of application possibilities is utilized. The ecosystems have been divided in five classes according to the ratio and thereby in accordance to our utilization of the total work capacity of various ecosystems. © 2010 Elsevier B.V.


Seidman L.J.,Harvard University | Nordentoft M.,Copenhagen University
Schizophrenia Bulletin | Year: 2015

A number of influences have converged that make this Special Theme Issue timely: "A New Direction: Considering Developmentally Sensitive Targets for Very Early Intervention in Schizophrenia". These factors include: 1. the substantial knowledge about premorbid developmental vulnerabilities to psychosis, especially regarding schizophrenia; 2. the promising results emerging from interventions during the clinical high-risk (CHR) phase of psychosis and; 3. the recognition that the CHR period is a relatively late phase of developmental derailment. These factors have together led to a perspective that even earlier intervention is warranted. This paper briefly summarizes the articles comprising the Special Theme including new data on early neurocognitive development, proposed potential targets for psychosocial and psychopharmacological interventions during the premorbid period as early as pregnancy, and ethical challenges. These thought experiments must be empirically tested, and the ethical challenges overcome as posed by the various interventions, which range from relatively low risk, supportive, psychosocial to higher risk, experimental, pharmacological interventions. All of the interventions proposed require careful study of ethics, safety, potential stigma, feasibility, efficacy and tolerability, and the meaning to the people involved. © 2015 The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.


Pedersen B.K.,Copenhagen University | Febbraio M.A.,Baker IDI Heart and Diabetes Institute
Nature Reviews Endocrinology | Year: 2012

During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases. © 2012 Macmillan Publishers Limited. All rights reserved.


Krarup C.,Copenhagen University
Clinical Neurophysiology | Year: 2011

Objective: The diagnosis of amyotrophic lateral sclerosis (ALS) includes demonstration of lower motor neuron (LMN) and upper motor neuron (UMN) involvement of bulbar and spinal muscles. Electromyography (EMG) is essential to confirm LMN affection in weak muscles, and to demonstrate changes in clinically non-involved muscles. The aim of the study was to determine the relative importance of ongoing (active) denervation, fasciculations, chronic partial denervation with reinnervation at weak effort and loss of motor units at maximal voluntary contraction (MVC) in ALS. Methods: EMG was carried out in weak and non-weak muscles in 220 patients suspected of ALS using concentric needle electrodes. Denervation activity and fasciculations in 966 muscles was quantified, the mean durations and amplitudes of motor unit potentials (MUPs) were compared to controls in 745 muscles, and the amplitudes and recruitment patterns at maximal voluntary effort were measured in 939 muscles. Twenty-five percent of patients had clinical involvement of 1 region, 42% of 2 regions and 33% of 3 regions. Clinically 65% had UMN involvement. Eighty-six percent of the patients had died on follow-up. Results: Denervation activity occurred in 72% of weak muscles but in only 45% of non-weak muscles. Fasciculations occurred in 56% of weak muscles and in 65% of non-weak muscles. MUPs showed reinnervation in 87-91% of weak and non-weak muscles and in 44% of muscles neurogenic MUPs occurred in the absence of denervation activity. In patients with clinical involvement of 1 region, combined EMG criteria increased the number of affected regions in 93%, and in 40% of patients with clinical involvement of 2 regions EMG increased the number of involved regions. Conclusions: Quantitative EMG confirmed widespread LMN involvement in patients with early ALS including clinically non-involved regions. These findings suggest that the maintenance of force is due to compensatory reinnervation in early disease and that this capacity may decline at later stages of ALS. Significance: These findings support a recent consensus report (the Awaji criteria) that EMG should have equivalent weight to clinical manifestations to indicate LMN involvement. The findings strongly indicate that spontaneous activity is insufficient to show LMN involvement in non-affected muscles at early stages of disease, and that analysis of MUPs are needed to document the distribution of LMN involvement. © 2010 International Federation of Clinical Neurophysiology.


Nielsen C.,Copenhagen University
Invertebrate Systematics | Year: 2012

The origin and radiation of the major metazoan groups can be elucidated by phylogenomic studies, but morphological evolution must be inferred from embryology and morphology of living organisms. According to the trochaea theory, protostomes are derived from a holoplanktonic gastraea with a circumblastoporal ring of downstream-collecting compound cilia (archaeotroch) and a nervous system comprising an apical ganglion and a circumblastoporal nerve ring. The pelago-benthic life cycle evolved through the addition of a benthic adult stage, with lateral blastopore closure creating a tube-shaped gut. The archaeotroch became differentiated as prototroch, metatroch and telotroch in the (trochophora) larva, but was lost in the adult. The apical ganglion was lost in the adult, as in all neuralians. Paired cerebral ganglia developed from the first micromere quartet. The circumblastoporal nerve became differentiated into a pair of ventral nerve cords with loops around mouth (the anterior part of the blastopore) and anus. Almost all new information about morphology and embryology fits the trochaea theory. The predicted presence of a perioral loop of the blastoporal nerve ring has now been demonstrated in two annelids. Alternative 'intercalation theories' propose that planktotrophic larvae evolved many times from direct-developing ancestors, but this finds no support from considerations of adaptation. © 2012 CSIRO.


Hatzakis N.S.,Copenhagen University
Biophysical Chemistry | Year: 2014

Biomolecular interactions regulate a plethora of vital cellular processes, including signal transduction, metabolism, catalysis and gene regulation. Regulation is encoded in the molecular properties of the constituent proteins; distinct conformations correspond to different functional outcomes. To describe the molecular basis of this behavior, two main mechanisms have been advanced: 'induced fit' and 'conformational selection'. Our understanding of these models relies primarily on NMR, computational studies and kinetic measurements. These techniques report the average behavior of a large ensemble of unsynchronized molecules, often masking intrinsic dynamic behavior of proteins and biologically significant transient intermediates. Single molecule measurements are emerging as a powerful tool for characterizing protein function. They offer the direct observation and quantification of the activity, abundance and lifetime of multiple states and transient intermediates in the energy landscape, that are typically averaged out in non-synchronized ensemble measurements. Here we survey new insights from single molecule studies that advance our understanding of the molecular mechanisms underlying biomolecular recognition. © 2013 Elsevier B.V.


Hansen S.,Copenhagen University
Journal of Applied Crystallography | Year: 2012

The structure factor and the effect of deviation from spherical symmetry are studied for elongated particles with axial ratios between 0.1 and 10. This is done using Monte Carlo simulation of the excluded-volume distance distribution function for ellipsoids of revolution, for cylinders and for cylinders with hemispherical end caps. The method suggested is general and is applicable to particles of any shape. The results of the calculations are compared with the Percus-Yevick formula [Percus & Yevick (1958), Phys. Rev. 110, 1-13] for hard spheres. The comparisons indicate that the Percus-Yevick formula should only be used for axial ratios close to 1. For larger deviations from spherical symmetry it is often better to use the excluded-volume distance distribution function for the particle, in combination with the single-particle distance distribution function, for the calculation of the structure factor. © 2012 International Union of Crystallography Printed in Singapore-all rights reserved.


Kastrup J.,Copenhagen University
Expert Review of Cardiovascular Therapy | Year: 2010

Not all patients with severe coronary artery disease can be treated satisfactorily with current recommended medications and revascularization techniques. Various vascular growth factors have the potential to induce angiogenesis in ischemic tissue. Clinical trials have only evaluated the effect of VEGF and FGF in patients with coronary artery disease. The initial small and unblinded studies with either recombinant growth factor proteins or genes encoding growth factors were encouraging, demonstrating both clinical improvement and evidence of angiogenesis. However, subsequent larger double-blind placebo-controlled trials could not confirm the initial high efficacy of either the growth factor protein or the gene therapy approaches observed in earlier small trials. The clinical studies so far have all been without any gene-related serious adverse events. Future trials will focus on whether an improvement in clinical results can be obtained with a cocktail of growth factors or by a combination of gene and stem cell therapy in patients with severe coronary artery disease, which cannot be treated effectively with current treatment strategies. © 2010 Expert Reviews Ltd.


Holst Sorensen M.C.,Copenhagen University
Frontiers in cellular and infection microbiology | Year: 2012

Bacteriophages are estimated to be the most abundant entities on earth and can be found in every niche where their bacterial hosts reside. The initial interaction between phages and Campylobacter jejuni, a common colonizer of poultry intestines and a major source of foodborne bacterial gastroenteritis in humans, is not well understood. Recently, we isolated and characterized a phage F336 resistant variant of C. jejuni NCTC11168 called 11168R. Comparisons of 11168R with the wildtype lead to the identification of a novel phage receptor, the phase variable O-methyl phosphoramidate (MeOPN) moiety of the C. jejuni capsular polysaccharide (CPS). In this study we demonstrate that the 11168R strain has gained cross-resistance to four other phages in our collection (F198, F287, F303, and F326). The reduced plaquing efficiencies suggested that MeOPN is recognized as a receptor by several phages infecting C. jejuni. To further explore the role of CPS modifications in C. jejuni phage recognition and infectivity, we tested the ability of F198, F287, F303, F326, and F336 to infect different CPS variants of NCTC11168, including defined CPS mutants. These strains were characterized by high-resolution magic angle spinning NMR spectroscopy. We found that in addition to MeOPN, the phase variable 3-O-Me and 6-O-Me groups of the NCTC11168 CPS structure may influence the plaquing efficiencies of the phages. Furthermore, co-infection of chickens with both C. jejuni NCTC11168 and phage F336 resulted in selection of resistant C. jejuni bacteria, which either lack MeOPN or gain 6-O-Me groups on their surface, demonstrating that resistance can be acquired in vivo. In summary, we have shown that phase variable CPS structures modulate phage infectivity in C. jejuni and suggest that the constant phage predation in the avian gut selects for changes in these structures leading to a continuing phage-host co-evolution.


Raggi C.,Liver Unit and Center for Autoimmune Liver Diseases | Invernizzi P.,Liver Unit and Center for Autoimmune Liver Diseases | Andersen J.B.,Copenhagen University
Journal of Hepatology | Year: 2015

Summary Clinical complexity, anatomic diversity and molecular heterogeneity of cholangiocarcinoma (CCA) represent a major challenge in the assessment of effective targeted therapies. Molecular and cellular mechanisms underlying the diversity of CCA growth patterns remain a key issue of clinical concern. Crucial questions comprise the nature of the CCA-origin, the initial target for cellular transformation as well as the relationship with the cancer stem cells (CSC) concept. Additionally, since CCA often develops in the context of an inflammatory milieu (cirrhosis and cholangitis), the stromal compartment or tumour microenvironment (TME) likely promotes initiation and progression of this malignancy, contributing to its heterogeneity. This review will emphasize the dynamic interplay between stem-like intrinsic and TME-extrinsic pathways, which may represent novel options for multi-targeted therapies in CCA.


Holst J.J.,Copenhagen University
Results and Problems in Cell Differentiation | Year: 2010

The glucagon gene is expressed not only in the alpha cells of the pancreatic islets but also in the endocrine cells of the intestinal epithelium (so-called L-cells), and in certain neurons of the brain stem. Whereas in the pancreas, glucagon, the hyperglycaemic hormone, is cleaved out of the 160 amino acid precursor, proglucagon, leaving behind proglucagon fragments (PG 1-30 and PG 72-158, the so-called major proglucagon fragment (MPGF)) that are probably inactive, the intestinal processing leads to the formation of glicentin (PG 1-69; action uncertain) and glucagon-like peptides 1 (PG 78-107amide, a potent incretin homone, regulating insulin secretion, glucagon secretion, gastrointestinal motility and appetite) and 2 (PG 126-158, a regulator of gut mucosal growth and integrity). The two prohormone convertases PC2 and PC1/3, respectively, are responsible for the differential processing. After their release, the hormones are eliminated mainly in the kidneys, but both GLP-2 and in particular GLP-1, but not glucagon, are metabolized both locally and in the circulation and liver by dipeptidyl peptidase 4 (DPP-4) which inactivates the peptides, suggesting that GLP-1 acts locally rather than in an endocrine manner. A number of transcription factors have been identified that can at least partly explain the differential cellular expression of the glucagon gene as well as the differential tissue-specific processing of the precursor. © 2010 Springer-Verlag Berlin Heidelberg.


Fahrenkrug J.,Copenhagen University
Results and Problems in Cell Differentiation | Year: 2010

Vasoactive intestinal polypeptide (VIP) is derived from a 170 amino acid precursor which in addition is processed to preproVIP 22-79, PHI, preproVIP 111-122 and preproVIP 156-170. All preproVIP-derived peptides have been shown in normal tissue and VIP-producing cell lines and elevated quantities occur in plasma and tumour tissues from patients with VIP-producing tumours. In some tissues the dibasic cleavage site after PHI is uncleaved resulting in a C-terminally extended form, PHV. PHI and VIP are present in a 1:1 molar ratio in large dense core vesicles and released in roughly equimolar amounts. Carboxyamidation of VIP and PHI is not critical and glycine-extended forms of both peptides have been demonstrated. Pituitary adenylate cyclase activating polypeptide (PACAP) is derived from a 170 amino acid long precursor, which gives rise to PACAP 38, PACAP 27 and PACAP related peptide (PRP). All peptides are present in tissue, the dominating form being PACAP 38. Prohormone convertase (PC) 1 and 2 seem to be involved in the processing of PACAP, except in the testes and ovary, where the PACAP precursor is substrate for PC4. © 2010 Springer-Verlag Berlin Heidelberg.


Bangsbo J.,Copenhagen University
Scandinavian journal of medicine & science in sports | Year: 2010

The present study investigated the performance effects and physiological adaptations over 16 weeks of recreational football training and continuous running for healthy untrained premenopausal women in comparison with an inactive control group [Football group (FG): n=21; running group (RG): n=18; CO: n=14]. Two weekly 1-h training sessions were performed in FG and RG. After 4 and 16 weeks of training VO(2max) was elevated (P<0.05) by 7% and 15%, respectively, in FG, and by 6% and 10%, respectively, in RG. After 16 weeks, Yo-Yo intermittent endurance level 2 performance was 33% and 19% better (P<0.05) for FG and 29% and 21% better (P<0.05) for RG than after 4 and 0 weeks, respectively. Peak sprinting speed was 12% higher (21.0 +/- 0.6 vs 18.8 +/- 0.7 km/h; P<0.05) for FG after the training period, whereas no difference was observed for RG. After 4 weeks citrate synthase (CS) and 3-hydroxyacyl-CoA dehydrogenase (HAD) activity was 9% and 8%, respectively, higher (P<0.05) than before training in FG with no further changes during the last 12 weeks. In RG, CS increased (P<0.05) by 12% after 4 weeks and no significant increase was observed for HAD. In FG, the number of capillaries per fiber was 18% higher (P<0.05) after 16 weeks (2.44 +/- 0.15 vs 2.07 +/- 0.05 cap/fiber), with no significant difference for RG. No differences were observed between 0 and 16 weeks for CO. In conclusion, recreational women's football leads to significant increases in VO(2max), performance and muscular adaptations throughout a 16-week training period. Thus, football can be used as an activity to elevate the physical capacity of untrained women.


Elbe A.M.,Copenhagen University
Scandinavian journal of medicine & science in sports | Year: 2010

This study explores whether inactive individuals can experience flow, a rewarding, psychological state, during an exercise intervention and if there are differences according to the type of intervention they perform. Furthermore, the study investigates if experiencing flow is connected to physiological improvements attained during the exercise intervention. The 12- to 16-week interventions included six randomized intervention groups, two female and four male groups performing continuous running, football, interval running and strength training. The results indicate that all six randomized exercise intervention groups experience rather high levels of flow regardless of whether the intervention is a team or individual sport. Differences in experiencing flow, worry and exertion as well as physiological improvements could be found for the different types of sports and the two genders, with the male football group having the highest score for physiological improvement and the lowest score for worry. A connection between experiencing flow and physiological improvement could not be found. Future research should investigate the influence that the participant's gender and also the type of sport have on experiencing flow, worry and perceived exertion. Furthermore, it should be investigated whether experiencing flow is linked to the long-term compliance of regular physical activity.


Jepsen P.,Aarhus University Hospital | Vilstrup H.,Aarhus University Hospital | Andersen P.K.,Copenhagen University
Hepatology | Year: 2015

Multistate models are models of disease progression that, for a patient group, define multiple outcome events, each of which may affect the time to develop another outcome event. Multistate models are highly relevant for studies of patients with cirrhosis; both the classical perception of cirrhosis as either compensated or decompensated and the recent, more complex models of cirrhosis progression are multistate models. Therefore, researchers who conduct clinical studies of patients with cirrhosis must realize that most of their research questions assume a multistate disease model. Failure to do so can result in severely biased results and bad clinical decisions. The analyses that can be used to study disease progression in a multistate disease model may be called competing risks analysis, named after the competing risks disease model, which is the simplest multistate disease model. In this review article, we introduce multistate disease models and competing risks analysis and explain why the standard armamentarium of Kaplan-Meier survival estimates and Cox regression sometimes gives bad answers to good questions. We also use real data to answer typical research questions about the course of cirrhosis and illustrate biases resulting from inadequate methods. Finally, we suggest statistical software packages that are helpful and accessible to the clinician-researcher. © 2014 by the American Association for the Study of Liver Diseases.


Helge J.W.,Copenhagen University
Acta Physiologica | Year: 2010

This review will focus on current data where substrate metabolism in arm and leg muscle is investigated and discuss the presence of higher carbohydrate oxidation and lactate release observed during arm compared with leg exercise. Furthermore, a basis for a possible difference in substrate partitioning between endogenous and exogenous substrate during arm and leg exercise will be debated. Moreover the review will probe if differences between arm and leg muscle are merely a result of different training status rather than a qualitative difference in limb substrate regulation. Along this line the review will address the available studies on low-intensity training performed separately with arm or legs or as whole-body training to evaluate if this leads to different adaptations in arm and leg muscle resulting in different substrate utilization patterns during separate arm or leg exercise at comparable workloads. Finally, the influence and capacity of low-intensity training to influence metabolic fitness in the face of a limited effect on aerobic fitness will be challenged. © 2010 Scandinavian Physiological Society.


Kasperbauer T.J.,Copenhagen University
Environmental Values | Year: 2016

Most philosophers and psychologists who have explored the psychology of climate change have focused only on motivational issues - getting people to act on what morality requires of them. This is misleading, however, because there are other psychological processes directed not at motivation but rather our ability to grasp the implications of climate change in a general way - what Stephen Gardiner has called the ‘grasping problem’. Taking the grasping problem as my departure point, I draw two conclusions from the relevant psychological literature: 1) ethicists and policy makers should focus less on changing individuals’ behaviours and more on changing policy; and 2) although solutions to climate change must come at the level of policy, progress on this front will be limited by incompatible moral norms. © 2016 The White Horse Press.


Van Hall G.,Copenhagen University
Acta Physiologica | Year: 2010

Lactate production in skeletal muscle has now been studied for nearly two centuries and still its production and functional role at rest and during exercise is much debated. In the early days skeletal muscle was mainly seen as the site of lactate production during contraction and lactate production associated with a lack of muscle oxygenation and fatigue. Later it was recognized that skeletal muscle not only played an important role in lactate production but also in lactate clearance and this led to a renewed interest, not the least from the Copenhagen School in the 1930s, in the metabolic role of lactate in skeletal muscle. With the introduction of lactate isotopes muscle lactate kinetics and oxidation could be studied and a simultaneous lactate uptake and release was observed, not only in muscle but also in other tissues. Therefore, this review will discuss in vivo human: (1) skeletal muscle lactate metabolism at rest and during exercise and suggestions are put forward to explain the simultaneous lactate uptake and release; and (2) lactate metabolism in the heart, liver, kidneys, brain, adipose tissue and lungs will be discussed and its potential importance in these tissues. © 2010 Scandinavian Physiological Society.


Krustrup P.,Copenhagen University
Scandinavian journal of medicine & science in sports | Year: 2010

We examined long-term musculoskeletal and cardiac adaptations elicited by recreational football (FG, n=9) and running (RG, n=10) in untrained premenopausal women in comparison with a control group (CG, n=9). Training was performed for 16 months ( approximately 2 weekly 1-h sessions). For FG, right and left ventricular end-diastolic diameters were increased by 24% and 5% (P<0.05), respectively, after 16 months. Right ventricular systolic function measured by tricuspid annular plane systolic excursion (TAPSE) increased (P<0.05) in FG after 4 months and further (P<0.05) after 16 months (15% and 32%, respectively). In RG and CG, cardiac structure, E/A and TAPSE remained unchanged. For FG, whole-body bone mineral density (BMD) was 2.3% and 1.3% higher (P<0.05) after 16 months, than after 4 and 0 months, respectively, with no changes for RG and CG. FG demonstrated substantial improvements (P<0.05) in fast (27% and 16%) and slow (16% and 17%) eccentric muscle strength and rapid force capacity (Imp30ms: 66% and 65%) after 16 months compared with 4 and 0 months, with RG improving Imp30ms by 64% and 46%. In conclusion, long-term recreational football improved muscle function, postural balance and BMD in adult women with a potential favorable influence on the risk of falls and fractures. Moreover, football training induced consistent cardiac adaptations, which may have implications for long-term cardiovascular health.


Tfelt-Hansen P.,Copenhagen University
Current Clinical Pharmacology | Year: 2012

Migraine is a common disorder with a female prevalence of 17% and a male prevalence of 9%. Migraine is most often disabling and the patients need treatment of the attacks. The introduction of triptans has been a revolution for many migraine patients but only a minority of patients use these specific drugs. The pharmacokinetics and efficacy and tolerability of triptans are reviewed. The triptans can most likely with advantage be combined with NSAIDs and prokinetic drugs. Among future drugs, CGRP receptor antagonists are the most promising. These drugs have shown excellent tolerability with no more adverse events than placebo, but only one quarter of migraine patients have been pain-free after 2 hours in phase III studies. The development of current CGRP antagonists has been stopped. © 2012 Bentham Science Publishers.


Gjerstorff M.F.,University of Southern Denmark | Andersen M.H.,Copenhagen University | Ditzel H.J.,University of Southern Denmark
Oncotarget | Year: 2015

Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer/testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic functions, including support of growth, survival and metastasis. This novel insight into the function of cancer/testis antigens has the potential to deliver more effective cancer vaccines. Moreover, immune targeting of oncogenic cancer/testis antigens in combination with conventional cytotoxic therapies or novel immunotherapies such as checkpoint blockade or adoptive transfer, represents a highly synergistic approach with the potential to improve patient survival.


Mathiasen S.,Copenhagen University
Nature Methods | Year: 2014

Proteoliposome reconstitution is a standard method to stabilize purified transmembrane proteins in membranes for structural and functional assays. Here we quantified intrareconstitution heterogeneities in single proteoliposomes using fluorescence microscopy. Our results suggest that compositional heterogeneities can severely skew ensemble-average proteoliposome measurements but also enable ultraminiaturized high-content screens. We took advantage of this screening capability to map the oligomerization energy of the β2-adrenergic receptor using ∼109-fold less protein than conventional assays.


Seymour P.A.,Copenhagen University
Review of Diabetic Studies | Year: 2014

Over the last decade, it has been discovered that the transcription factor Sox9 plays several critical roles in governing the development of the embryonic pancreas and the homeostasis of the mature organ. While analysis of pancreata from patients affected by the Sox9 haploinsufficiency syndrome campomelic dysplasia initially alluded to a functional role of Sox9 in pancreatic morphogenesis, transgenic mouse models have been instrumental in mechanistically dissecting such roles. Although initially defined as a marker and maintenance factor for pancreatic progenitors, Sox9 is now considered to fulfill additional indispensable functions during pancreogenesis and in the postnatal organ through its interactions with other transcription factors and signaling pathways such as Fgf and Notch. In addition to maintaining both multipotent and bipotent pancreatic progenitors, Sox9 is also required for initiating endocrine differentiation and maintaining pancreatic ductal identity, and it has recently been unveiled as a key player in the initiation of pancreatic cancer. These functions of Sox9 are discussed in this article, with special emphasis on the knowledge gained from various loss-of-function and lineage tracing mouse models. Also, current controversies regarding Sox9 function in healthy and injured adult pancreas and unanswered questions and avenues of future study are discussed.


Idorn T.,Copenhagen University
The Journal of clinical endocrinology and metabolism | Year: 2014

The affect of the kidneys in elimination and degradation of intact incretin hormones and their truncated metabolites is unclear. To evaluate elimination and degradation of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in patients with dialysis-dependent kidney failure. Twelve non-diabetic patients treated with chronic hemodialysis and 12 control subjects were examined in a double-blind, randomized, matched observational study at the Department of Nephrology, Rigshospitalet, University of Copenhagen, Denmark. Over 4 separate study days, synthetic human GIP or GLP-1 was infused with or without concurrent inhibition of dipeptidyl peptidase 4 using sitagliptin or placebo. Plasma concentrations of glucose, insulin, glucagon, and intact and total forms of GLP-1 or GIP were measured repeatedly. Plasma half-life (T1/2), metabolic clearance rate (MCR), area under curve, and volume of distribution for intact and metabolite levels of GLP-1 and GIP were calculated. Fasting concentrations of intact GLP-1 and GIP were increased in dialysis patients (P < .001) whereas fasting levels of GLP-1 and GIP metabolites did not differ between groups (P > .738). MCRs of intact GLP-1 and GIP, and the GLP-1 metabolite were reduced in dialysis patients on the placebo day (P < .009), and T1/2 of intact and metabolite forms of GLP-1 and GIP were comparable between groups (P > .121). Unexpectedly, degradation and elimination of the intact and metabolite forms of GLP-1 and GIP seemed preserved, although reduced, in patients with dialysis-dependent kidney failure.


Vangkilde S.,Copenhagen University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

Temporal expectation is expectation with respect to the timing of an event such as the appearance of a certain stimulus. In this paper, temporal expectancy is investigated in the context of the theory of visual attention (TVA), and we begin by summarizing the foundations of this theoretical framework. Next, we present a parametric experiment exploring the effects of temporal expectation on perceptual processing speed in cued single-stimulus letter recognition with unspeeded motor responses. The length of the cue-stimulus foreperiod was exponentially distributed with one of six hazard rates varying between blocks. We hypothesized that this manipulation would result in a distinct temporal expectation in each hazard rate condition. Stimulus exposures were varied such that both the temporal threshold of conscious perception (t0 ms) and the perceptual processing speed (v letters s(-1)) could be estimated using TVA. We found that the temporal threshold t0 was unaffected by temporal expectation, but the perceptual processing speed v was a strikingly linear function of the logarithm of the hazard rate of the stimulus presentation. We argue that the effects on the v values were generated by changes in perceptual biases, suggesting that our perceptual biases are directly related to our temporal expectations.


Skou S.,Copenhagen University | Gillilan R.E.,Cornell University | Ando N.,Massachusetts Institute of Technology
Nature Protocols | Year: 2014

With recent advances in data analysis algorithms, X-ray detectors and synchrotron sources, small-angle X-ray scattering (SAXS) has become much more accessible to the structural biology community. Although limited to ∼10 Å resolution, SAXS can provide a wealth of structural information on biomolecules in solution and is compatible with a wide range of experimental conditions. SAXS is thus an attractive alternative when crystallography is not possible. Moreover, advanced use of SAXS can provide unique insight into biomolecular behavior that can only be observed in solution, such as large conformational changes and transient protein-protein interactions. Unlike crystal diffraction data, however, solution scattering data are subtle in appearance, highly sensitive to sample quality and experimental errors and easily misinterpreted. In addition, synchrotron beamlines that are dedicated to SAXS are often unfamiliar to the nonspecialist. Here we present a series of procedures that can be used for SAXS data collection and basic cross-checks designed to detect and avoid aggregation, concentration effects, radiation damage, buffer mismatch and other common problems. Human serum albumin (HSA) serves as a convenient and easily replicated example of just how subtle these problems can sometimes be, but also of how proper technique can yield pristine data even in problematic cases. Because typical data collection times at a synchrotron are only one to several days, we recommend that the sample purity, homogeneity and solubility be extensively optimized before the experiment. © 2014 Nature America, Inc. All rights reserved.


Objectives The aim of this article is to provide an overview of the International Caries Detection and Assessment System (ICDAS) and its associated International Caries Classification and Management System (ICCMS ™), explain the evolution of these systems over the past decade and outline how they are being used for staging of the caries process in order to enable dentists to manage caries appropriately. Methods the article outlines and references the key steps in development of these systems. Results ICDAS employs an evidence-based and preventively oriented approach, is a detection and assessment system classifying stages of the caries process on the basis of histological extent and activity, is designed for use in the four domains of clinical practice, education, research and public health and provides all stakeholders with a common language for staging caries. Over a decade ICDAS has evolved to comprise a number of approved, compatible 'formats', supports decision making at both individual and public health levels and has generated the ICCMS™ to enable improved long-term caries outcomes. A range of further developments are in train, to assist with information capture and making clinical systems simpler and more practice friendly. Conclusion ICDAS provides flexible and increasingly internationally adopted methods for classifying stages of the caries process and the activity status of lesions which can be incorporated into the ICCMS™. The ICCMS ™ provides options to enable dentists to integrate and synthesize tooth and patient information, including caries risk status, in order to plan, manage and review caries in clinical and public health practice. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.


Palmgren M.G.,Copenhagen University | Nissen P.,University of Aarhus
Annual Review of Biophysics | Year: 2011

P-type ATPases form a large superfamily of cation and lipid pumps. They are remarkably simple with only a single catalytic subunit and carry out large domain motions during transport. The atomic structure of P-type ATPases in different conformations, together with ample mutagenesis evidence, has provided detailed insights into the pumping mechanism by these biological nanomachines. Phylogenetically, P-type ATPases are divided into five subfamilies, P1P5. These subfamilies differ with respect to transported ligands and the way they are regulated. © 2011 by Annual Reviews. All rights reserved.


Ziebe S.,Copenhagen University
Reproduction, Fertility and Development | Year: 2014

Morphometric and morphokinetic approaches toward embryo quality assessment have for many years been difficult due to technical limitations. Today, with improvements in laboratory techniques and subsequent quality, we have a better understanding of the morphometric and kinetics of embryo development. Fertility clinics are moving from "sensing" embryo quality to measuring embryo quality - and this is happening every day in fertility clinics all over the world. However, we cannot select for something that is not there. In daily clinical life it is almost never a question of selecting the optimal embryo, but rather choosing and prioritising between the available embryos. Data suggest that only approximately 5% of aspirated human oocytes have the competence to implant and develop into a child and that, in most treatment cycles, there is no oocyte capable of implanting. The most likely outcome is a negative pregnancy test, no matter what we choose in the laboratory. Still, both with the increasing complexity of infertile patients treated today and the important focus on reducing multiple pregnancies, it becomes increasingly important to improve our ability to predict the developmental competence of each embryo. This involves an improved understanding of the basic biology controlling early embryonic development and, over the years, many groups have tried to identify parameters reflecting embryonic competence. © IETS 2014.


Hansen C.R.,Copenhagen University
Current Opinion in Pulmonary Medicine | Year: 2012

PURPOSE OF REVIEW: Stenotrophomonas maltophilia can cause persistent airway colonization and chronic infection in cystic fibrosis (CF) patients. The clinical effect of chronic S. maltophilia infection is still a matter of debate. The purpose of the review is to summarize studies published during the last 1.5 years with a focus on whether S. maltophilia should be regarded as a 'true' CF pathogen. RECENT FINDINGS: Studies concerning the microbiological characteristics of this microorganism with special focus on identification, virulence factors, cross-infection and resistance pattern, and studies on clinical effects of chronic infection, specifically serological responses to this infection, negative effects on the clinical status and possible effects of antibiotic treatment have been reviewed. SUMMARY: S. maltophilia can be identified with certainty, has well-described virulence factors, is capable of cross-infection and often shows multiresistance. Although CF patients with chronic S. maltophilia infection have lower lung function parameters compared with other CF patients and experience more exacerbations, chronic S. maltophilia infection in itself was not associated with a worse clinical outcome. True, pathogenic effects of S. maltophilia could not be found, but the presence of chronic S. maltophilia could be a marker of more pronounced lung disease in affected patients. © 2012 Wolters Kluwer Health | Lippincott Williams &Wilkins.


Holst J.J.,Novo Nordisk AS | Vilsboll T.,Copenhagen University
Diabetes, Obesity and Metabolism | Year: 2013

Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase insulin release and suppress glucagon secretion in a glucose-dependent manner, thus conferring glycaemic control with a low incidence of hypoglycaemia. GLP-1RAs also promote weight loss, and have beneficial effects on markers of β cell function, lipid levels, blood pressure and cardiovascular risk markers. However, the durability of their effectiveness is unknown and, compared with insulin, the antihyperglycaemic efficacy of GLP-1RAs is limited. The combination of a GLP-1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic potential of GLP-1RA-insulin combination therapy, typically showing beneficial effects on glycaemic control and body weight, with a low incidence of hypoglycaemia and, in established insulin therapy, facilitating reductions in insulin dose. In this review, the physiological and pharmacological rationale for using GLP-1RA and insulin therapies in combination is discussed, and data from clinical studies that have assessed the efficacy and safety of this treatment strategy are outlined. © 2012 Blackwell Publishing Ltd.


Kongsgaard M.,Copenhagen University
The American journal of sports medicine | Year: 2010

BACKGROUND: Patellar tendinopathy is characterized by pathologic abnormalities. Heavy slow resistance training (HSR) is effective in the management of patellar tendinopathy, but the underlying functional mechanisms remain elusive. PURPOSE: To investigate fibril morphology and mechanical properties in patellar tendinopathy and the effect of HSR on these properties. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Eight male patients with patellar tendinopathy completed 12 weeks of HSR. Nine healthy subjects served as controls. Assessments were conducted at baseline and at 12 weeks. Patients assessed symptoms/function and maximal tendon pain during activity. Tendon biopsy samples were analyzed for fibril density, volume fraction, and mean fibril area. Tendon mechanical properties were assessed using force and ultrasonography samplings. RESULTS: Patients improved in symptoms/function (P = .02) and maximal tendon pain during activity (P = .008). Stiffness and modulus of control and tendinopathy tendons were similar at baseline. Stiffness remained unaffected in control tendons (3487 +/- 392 to 3157 +/- 327 N/mm, P = .57) but declined in tendinopathic tendons at 12 weeks (3185 +/- 187 to 2701 +/- 201 N/mm, P = .04). At baseline, fibril volume fraction was equal, fibril density smaller (P = .03), and mean fibril area tended to be higher in tendinopathy versus controls (P = .07). Fibril morphology remained unchanged in controls but fibril density increased (70% +/- 18%, P = .02) and fibril mean area decreased (-26% +/- 21%, P = .04) in tendinopathic tendons after HSR. CONCLUSION: Fibril morphology is abnormal in tendinopathy, but tendon mechanical properties are not. Clinical improvements after HSR were associated with changes in fibril morphology toward normal fibril density and mean fibril area. Heavy slow resistance training improved the clinical outcome of patellar tendinopathy, and these improvements were associated with normalization of fibril morphology, most likely due to a production of new fibrils.


Rand K.D.,Copenhagen University | Zehl M.,University of Vienna | Jorgensen T.J.D.,University of Southern Denmark
Accounts of Chemical Research | Year: 2014

ConspectusProteins are dynamic molecules that exhibit conformational flexibility to function properly. Well-known examples of this are allosteric regulation of protein activity and ligand-induced conformational changes in protein receptors. Detailed knowledge of the conformational properties of proteins is therefore pertinent to both basic and applied research, including drug development, since the majority of drugs target protein receptors and a growing number of drugs introduced to the market are therapeutic peptides or proteins. X-ray crystallography provides a static picture at atomic resolution of the lowest-energy structure of the native ensemble. There is a growing need for sensitive analytical tools to explore all of the significant molecular structures in the conformational landscape of proteins. Hydrogen/deuterium exchange monitored by mass spectrometry (HDX-MS) has recently emerged as a powerful method for characterizing protein conformational dynamics. The basis of this method is the fact that backbone amides in stable hydrogen-bonded structures (e.g., α-helices and β-sheets) are protected against exchange with the aqueous solvent. All protein structures are dynamic, however, and eventually all of the protecting hydrogen bonds will transiently break as the protein-according to thermodynamic principles-cycles through partially unfolded states that correspond to excited free energy levels. As a result, all of the backbone amides will eventually become temporarily solvent-exposed and exchange-competent over time. Consequently, a folded protein in D2O will gradually incorporate deuterium into its backbone amides, and the kinetics of the process can be readily monitored by mass spectrometry. The deuterium uptake kinetics for the intact protein (global exchange kinetics) represents the sum of the exchange kinetics for the individual backbone amides. Local exchange kinetics is typically achieved by using pepsin digestion under quench conditions (i.e., under cold acidic conditions where the amide hydrogen exchange rate is slowed by many orders of magnitude). The ability to localize the individual deuterated residues (the spatial resolution) is determined by the size (typically ∼7-15 residues) and the number of peptic peptides. These peptides provide a relatively coarse-grained picture of the protein dynamics. A fundamental understanding of the relationship between protein function/dysfunction and conformational dynamics requires in many cases higher resolution and ultimately single-residue resolution.In this Account, we summarize our efforts to achieve single-residue deuterium levels in proteins by electron-based or laser-induced gas-phase fragmentation methods. A crucial analytical requirement for this approach is that the pattern of deuterium labeling from solution is retained in the gas-phase fragment ions. It is therefore essential to control and minimize any occurrence of gas-phase randomization of the solution deuterium label (H/D scrambling) during the MS experiment. For this purpose, we have developed model peptide probes to accurately measure the onset and extent of H/D scrambling. Our analytical procedures to control the occurrence of H/D scrambling are detailed along with the physical parameters that induce it during MS analysis. In light of the growing use of gas-phase dissociation experiments to measure the HDX of proteins in order to obtain a detailed characterization and understanding of the dynamic conformations and interactions of proteins at the molecular level, we discuss the perspectives and challenges of future high-resolution HDX-MS methodology. © 2014 American Chemical Society.


Glaser L.,Copenhagen University
Classical and Quantum Gravity | Year: 2014

Recently a definition for a Lorentz invariant operator approximating the d'Alembertian in d-dimensional causal set spacetimes has been proposed. This operator contains several dimension-dependent constants which have been determined for d = 2,⋯ 7. In this note we derive closed form expressions for these constants, which are valid in all dimensions. Using these we prove that the causal set action in any dimension can be defined through this discrete d'Alembertian, with a dimension independent prefactor. © 2014 IOP Publishing Ltd.


Axelsen M.B.,Copenhagen University
Scandinavian journal of rheumatology | Year: 2013

To investigate the responsiveness to treatment and the reliability of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in rheumatoid arthritis (RA) knee joints. DCE-MRI was performed in 12 clinically active RA knee joints before and 1, 7, 30, and 180 days after intra-articular injection with 80 mg methylprednisolone. Using semi-automated image processing software, DCE-MRI parameters, including the initial rate of enhancement (IRE) and maximal enhancement (ME), were generated for three regions of interest (ROIs): 'Whole slice', 'Quick ROI', and 'Precise ROI'. The smallest detectable difference (SDD), the smallest detectable change (SDC), and intra- and inter-reader intraclass correlation coefficients (ICCs) were used to assess the reliability of DCE-MRI. Responsiveness to treatment was assessed by the standardized response mean (SRM). In all patients clinical remission of the knee was achieved at day 7. All DCE-MRI parameters decreased from day 0 to day 7. Using the Quick and Precise ROI methods, respectively, IRE decreased by 63% and 69%, ME decreased by 11% and 11%, N decreased by 55% and 57%, and IRE × N decreased by 84% and 85%. The intra- and inter-reader ICCs were very high (0.96-1.00). The decrease in DCE-MRI parameters was larger than the SDC for all patients. SRM was large for all parameters, ranging from -1.04 to -2.40. When the Whole slice ROI method was used, no parameters were responsive to treatment. DCE-MRI analysed using semi-automatic software is a reliable and responsive tool for assessing treatment in RA knees joints. Rough manual delineation of the joint to omit enhancement artefacts is necessary.


Skibsted L.H.,Copenhagen University
Nitric Oxide - Biology and Chemistry | Year: 2011

Preservation of meat with nitrite or nitrate has become important to mankind in controlling meat spoilage and in producing safe and palatable meat products with good keeping properties even at ambient temperature. Nitric oxide was early recognised as pivotal for colour and colour stability of such meat products. Later specific effects on microbial growth became evident, followed by an understanding of nitric oxide as an antioxidant in processed meat, while a future recognition of nitric oxide as modulator of transmetallisation reactions in meat seems possible. Central for all these functions of nitric oxide in meat is the heme cavity in the meat pigment myoglobin with its facile conversions among reactive oxygen and nitrogen species in certain cases assisted by curing additives such as ascorbate and with a possible involvement of nitroxyl.


Middle Ordovician (late Dapingian-Darriwilian) conodonts from the Shallow Bay and Green Point formations, Cow Head Group, and the Lower Head Formation are recorded from three sections in Gros Morne National Park. The collection was investigated to clarify local age relationships between the uppermost part of the Cow Head Group and the interbedded to overlying sediments of the Lower Head Formation. Conodonts from St. Pauls Inlet North section indicate a middle Dapingian age for the upper lower Bed 13, latest Dapingian to early Darriwilian age for the upper Bed 13, an early Darriwilian (Dw 1) age for the top beds or Bed 15 of the Shallow Bay Formation at Lower Head, and the Lower Head Formation is referred to the Darriwilian. The uppermost part of the lower Bed 13 contains Periodon hankensis n. sp., Gothodus sp. A, and Diaphorodus delicatus followed by Periodon macrodentatus, Ansella longicuspica, Erraticodon n. sp. A, and Spinodus wardi n. sp. in the lowermost part of upper Bed 13. The fauna with P. macrodentatus is referred to the newly established Periodon macrodentatus conodont (phylo-)Zone, which is used for global correlation. The uppermost fauna in the Cow Head Group, i.e., Bed 15, includes Histiodella holodentata, Nealeodus martinpointensis, Oistodella pulchra, Dzikodus peavyi, and Yangtzeplacognathus n. sp. A, which are included in the Histiodella holodentata conodont (Bio-)Subzone of the Periodon macrodentatus Zone. Nealeodus is a new genus introduced here; Periodon hankensis n. sp. and Spinodus wardi n. sp. are new species described from the beds 13 and 15, respectively, in the Cow Head Group; Drepanodus aff. D. giganteus, Drepanodus aff. D. robustus, Erraticodon n. sp. A, Protopanderodus cf. P. cooperi, P. cf. P. varicostatus, and Yangtzeplacognathus n. sp. A are taxa referred to in open nomenclature.


Andersen S.P.,Copenhagen University
Muscle & nerve | Year: 2013

We investigated the effect of high-intensity exercise on plasma creatine kinase (CK) in patients with muscular dystrophies. Fourteen patients with Becker (BMD), facioscapulohumeral (FSHD), or limb-girdle type 2 (LGMD2) muscular dystrophy, and 8 healthy subjects performed 5 cycling tests: an incremental max test, and tests at 65%, 75%, 85%, and 95% of maximal oxygen uptake (VO2max ). Heart rate and oxygen consumption were measured during the tests, and plasma CK was measured before, immediately after, and 24 hours after exercise. All subjects were able to perform high-intensity exercise at the different levels. In patients with LGMD2 and FSHD, CK normalized 24 hours after exercise compared with the pre-exercise value, whereas those with BMD and healthy controls had elevated CK values 24 hours after exercise. The findings suggest that high-intensity exercise is generally well tolerated in patients with LGMD2 and FSHD, whereas those with BMD may be more prone to exercise-induced damage. Copyright © 2013 Wiley Periodicals, Inc.


Recent predictions of absolute binding free energies of host-guest complexes in aqueous solution using electronic structure theory have been encouraging for some systems, while other systems remain problematic. In this paper I summarize some of the many factors that could easily contribute 1-3 kcal mol-1 errors at 298 K: three-body dispersion effects, molecular symmetry, anharmonicity, spurious imaginary frequencies, insufficient conformational sampling, wrong or changing ionization states, errors in the solvation free energy of ions, and explicit solvent (and ion) effects that are not well-represented by continuum models. While I focus on binding free energies in aqueous solution the approach also applies (with minor adjustments) to any free energy difference such as conformational or reaction free energy differences or activation free energies in any solvent. © the Owner Societies 2015.


Bottcher L.,Copenhagen University
Child Neuropsychology | Year: 2010

White matter lesions are often seen in children with spastic cerebral palsy (CP). Evidence points to specific impairment of attentional, visuospatial, and executive functions; although both attention and executive functions are relatively unexplored in spastic CP. The few recent studies on language functions in mild or moderate CP point to well-functioning language. The presence of specific cognitive impairments may, in part, explain why children with spastic CP have a higher risk of learning disabilities and problems in peer relations. However, to understand the development of cognitive impairments, it is necessary to include how social participation feeds back on cognitive processes. © 2010 Psychology Press.


Harris K.,University of California at Berkeley | Nielsen R.,University of California at Berkeley | Nielsen R.,Copenhagen University
Genome Research | Year: 2014

About 2% of human genetic polymorphisms have been hypothesized to arise via multinucleotide mutations (MNMs), complex events that generate SNPs at multiple sites in a single generation. MNMs have the potential to accelerate the pace at which single genes evolve and to confound studies of demography and selection that assume all SNPs arise independently. In this paper, we examine clustered mutations that are segregating in a set of 1092 human genomes, demonstrating that the signature ofMNMbecomes enriched as large numbers of individuals are sampled. We estimate the percentage of linked SNP pairs that were generated by simultaneous mutation as a function of the distance between affected sites and show that MNMs exhibit a high percentage of transversions relative to transitions, findings that are reproducible in data from multiple sequencing platforms and cannot be attributed to sequencing error. Among tandem mutations that occur simultaneously at adjacent sites, we find an especially skewed distribution of ancestral and derived alleles, with GC→AA, GA→TT, and their reverse complements making up 27% of the total. These mutations have been previously shown to dominate the spectrum of the error-prone polymerase Pol ζ, suggesting that low-fidelity DNA replication by Pol ζ is at least partly responsible for the MNMs that are segregating in the human population. We develop statistical estimates of MNM prevalence that can be used to correct phylogenetic and population genetic inferences for the presence of complex mutations. © 2014 Totoki et al.; Published by Cold Spring Harbor Laboratory Press.


Introduction: If a drug has a slow dissociation from the receptor this can result in a long duration of effect and a slow effect. The long duration of the antimigraine effect of dihydroergotamine (DHE) has been reported previously whereas a possible slow onset of DHE's antimigraine effect, which is the subject of this review, has only rarely been mentioned. Methods: Eight randomised, controlled trials (RCT) with DHE for acute treatment with migraine were selected from the literature. The speed of the effect of DHE in migraine was evaluated by plotting the effect up to four hours against time. Findings: Subcutaneous DHE 1mg was inferior to subcutaneous sumatriptan 6mg for headache relief for the first two hours but equally effective after three hours. After intranasal DHE 2mg the mean therapeutic gain increased slowly up to four hours. For orally inhaled DHE 0.5 mg there was a considerable time lag between therapeutic gain (maximum after two hours) and plasma concentrations of DHE (Tmax12 min). Conclusion: DHE has a slow dissociation from the receptor; and this basic attribute of the drug is the most likely cause of the general relatively slow anti-migraine effect of DHE. © 2013 International Headache Society.


In 1937, August Krogh discovered a powerful active Cl(-) uptake mechanism in frog skin. After WWII, Hans Ussing continued the studies on the isolated skin and discovered the passive nature of the chloride uptake. The review concludes that the two modes of transport are associated with a minority cell type denoted as the γ-type mitochondria-rich (MR) cell, which is highly specialized for epithelial Cl(-) uptake whether the frog is in the pond of low [NaCl] or the skin is isolated and studied by Ussing chamber technique. One type of apical Cl(-) channels of the γ-MR cell is activated by binding of Cl(-) to an external binding site and by membrane depolarization. This results in a tight coupling of the uptake of Na(+) by principal cells and Cl(-) by MR cells. Another type of Cl(-) channels (probably CFTR) is involved in isotonic fluid uptake. It is suggested that the Cl(-) channels serve passive uptake of Cl(-) from the thin epidermal film of fluid produced by mucosal glands. The hypothesis is evaluated by discussing the turnover of water and ions of the epidermal surface fluid under terrestrial conditions. The apical Cl(-) channels close when the electrodiffusion force is outwardly directed as it is when the animal is in the pond. With the passive fluxes eliminated, the Cl(-) flux is governed by active transport and evidence is discussed that this is brought about by an exchange of cellular HCO(3) (-) with Cl(-) of the outside bath driven by an apical H(+) V-ATPase. © 2011 The Author. Acta Physiologica © 2011 Scandinavian Physiological Society.


Maarbjerg S.J.,Copenhagen University
Acta physiologica (Oxford, England) | Year: 2011

Exercise counteracts insulin resistance and improves glucose homeostasis in many ways. Apart from increasing muscle glucose uptake quickly, exercise also clearly increases muscle insulin sensitivity in the post-exercise period. This review will focus on the mechanisms responsible for this increased insulin sensitivity. It is believed that increased sarcolemmal content of the glucose transporter GLUT4 can explain the phenomenon to some extent. Surprisingly no improvement in the proximal insulin signalling pathway is observed at the level of the insulin receptor, IRS1, PI3K or Akt. Recently more distal signalling component in the insulin signalling pathway such as aPKC, Rac1, TBC1D4 and TBC1D1 have been described. These are all affected by both insulin and exercise which means that they are likely converging points in promoting GLUT4 translocation and therefore possible candidates for regulating insulin sensitivity after exercise. Whereas TBC1D1 does not appear to regulate insulin sensitivity after exercise, correlative evidence in contrast suggests TBC1D4 to be a relevant candidate. Little is known about aPKC and Rac1 in relation to insulin sensitivity after exercise. Besides mechanisms involved in signalling to GLUT4 translocation, factors influencing the trans-sarcolemmal glucose concentration gradient might also be important. With regard to the interstitial glucose concentration microvascular perfusion is particular relevant as correlative evidence supports a connection between insulin sensitivity and microvascular perfusion. Thus, there are new candidates at several levels which collectively might explain the phenomenon. © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society.


Novak I.,Copenhagen University
Acta physiologica (Oxford, England) | Year: 2011

Intracellular ATP, the energy source for many reactions, is crucial for the activity of plasma membrane pumps and, thus, for the maintenance of transmembrane ion gradients. Nevertheless, ATP and other nucleotides/nucleosides are also extracellular molecules that regulate diverse cellular functions, including ion transport. In this review, I will first introduce the main components of the extracellular ATP signalling, which have become known as the purinergic signalling system. With more than 50 components or processes, just at cell membranes, it ranks as one of the most versatile signalling systems. This multitude of system components may enable differentiated regulation of diverse epithelial functions. As epithelia probably face the widest variety of potential ATP-releasing stimuli, a special attention will be given to stimuli and mechanisms of ATP release with a focus on exocytosis. Subsequently, I will consider membrane transport of major ions (Cl(-) , HCO(3)(-) , K(+) and Na(+) ) and integrate possible regulatory functions of P2Y2, P2Y4, P2Y6, P2Y11, P2X4, P2X7 and adenosine receptors in some selected epithelia at the cellular level. Some purinergic receptors have noteworthy roles. For example, many studies to date indicate that the P2Y2 receptor is one common denominator in regulating ion channels on both the luminal and basolateral membranes of both secretory and absorptive epithelia. In exocrine glands though, P2X4 and P2X7 receptors act as cation channels and, possibly, as co-regulators of secretion. On an organ level, both receptor types can exert physiological functions and together with other partners in the purinergic signalling, integrated models for epithelial secretion and absorption are emerging. © 2011 The Author. Acta Physiologica © 2011 Scandinavian Physiological Society.


Zahavi D.,Copenhagen University
Inquiry | Year: 2010

When it comes to understanding the nature of social cognition, we have-according to the standard view-a choice between the simulation theory, the theory-theory or some hybrid between the two. The aim of this paper is to argue that there are, in fact, other options available, and that one such option has been articulated by various thinkers belonging to the phenomenological tradition. More specifically, the paper will contrast Lipps' account of empathy-an account that has recently undergone something of a revival in the hands of contemporary simulationists-with various accounts of empathy found in the phenomenological tradition. I discuss the way Lipps was criticized by Scheler, Stein and Husserl, and outline some of the core features of their, at times divergent, alternatives. I then proceed by considering how their basic take on empathy and social cognition was taken up and modified by Schutz-a thinker whose contribution to the analysis of interpersonal understanding has been unjustly neglected in recent years. © 2010 Taylor & Francis.


Lyng K.M.,Copenhagen University
International Journal of Medical Informatics | Year: 2013

This paper presents a case study of clinical guidance within oncology clinics. Close to all patients treated within the observed clinics were treated according to clinical practice guidelines in the form of either a research or a standard treatment protocol. The clinical practice guideline artifacts were however rarely applied in clinical practice. It was first when the guidelines were translated and transformed into second order guiding artifacts (SOGAs) they were applied. The SOGAs applied in clinical practice were activity specific holding space for relevant documentation. The transformation from clinical practice guideline to SOGA was executed according to a standard operating procedure. A wide number of physical features were applied to support quick overview and application in clinical practice. The clinicians were actively participating in the translation and transformation process obtaining ownership to the resulting artifacts. The implications for computerization of clinical practice guidelines are discussed. © 2012 Elsevier Ireland Ltd.


Penninga L.,Copenhagen University
The Cochrane database of systematic reviews | Year: 2013

Heart transplantation has become a valuable and well-accepted treatment option for end-stage heart failure. Rejection of the transplanted heart by the recipient's body is a risk to the success of the procedure, and life-long immunosuppression is necessary to avoid this. Clear evidence is required to identify the best, safest and most effective immunosuppressive treatment strategy for heart transplant recipients. To date, there is no consensus on the use of immunosuppressive antibodies against T-cells for induction after heart transplantation. To review the benefits, harms, feasibility and tolerability of immunosuppressive T-cell antibody induction versus placebo, or no antibody induction, or another kind of antibody induction for heart transplant recipients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2012), MEDLINE (Ovid) (1946 to November Week 1 2012), EMBASE (Ovid) (1946 to 2012 Week 45), ISI Web of Science (14 November 2012); we also searched two clinical trial registers and checked reference lists in November 2012. We included all randomised clinical trials (RCTs) (24/90 (27%) versus 10/95 (11%); RR 2.43; 95% CI 1.01 to 5.86; I(2) 28%). For all of these differences in acute rejection, trial sequential alpha-spending boundaries were not crossed and the required information sizes were not reached when trial sequential analysis was performed, at a high risk of bias. Hence, more RCTs are needed to assess the benefits and harms of T-cell antibody induction for heart-transplant recipients. Such trials ought to be conducted with low risks of systematic and random error.


Goetze J.P.,Copenhagen University
Clinical Chemistry | Year: 2012

BACKGROUND: Plasma cardiac natriuretic peptides and peptide fragments from their molecular precursors are markers of heart disease. Clinical studies have defined the current diagnostic utility of these markers, whereas biochemical elucidation of peptide structure and posttranslational processing has revealed new plasma peptide forms of potential clinical use. CONTENT: Natriuretic propeptide structures undergo variable degrees of endo- and exoproteolytic cleavages as well as amino acid modifications, which leave the plasma phase of the peptides highly heterogeneous and dependent on cardiac pathophysiology and capacity. An ongoing characterization of the molecular heterogeneity may not only help us to appreciate the biosynthetic capacity of the endocrine heart but may also lead to the discovery of new and more disease-specific targets for future molecular diagnosis. SUMMARY: Peptides derived from pro-atrial natriuretic peptide and pro-B-type natriuretic peptide are useful plasma markers in heart failure. New data have defined cardiac myocytes as competent endocrine cells in posttranslational processing and cellular secretion. © 2011 American Association for Clinical Chemistry.


Amorim Adegboye A.R.,Copenhagen University
The Cochrane database of systematic reviews | Year: 2013

Weight retention after pregnancy may contribute to obesity. It is known that diet and exercise are recommended components of any weight loss programme in the general population. However, strategies to achieve healthy body weight among postpartum women have not been adequately evaluated. The objectives of this review were to evaluate the effect of diet, exercise or both for weight reduction in women after childbirth, and to assess the impact of these interventions on maternal body composition, cardiorespiratory fitness, breastfeeding performance and other child and maternal outcomes. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2012) and LILACS (31 January 2012). We scanned secondary references and contacted experts in the field. We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 30 April 2013 and added the results to the awaiting classification section of the review. All published and unpublished randomised controlled trials (RCTs) and quasi-randomised trials of diet or exercise or both, among women during the postpartum period. Both review authors independently assessed trial quality and extracted data. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for continuous data. Data were analysed with a fixed-effect model. A random-effects model was used in the presence of heterogeneity. Fourteen trials were included, but only 12 trials involving 910 women contributed data to outcome analysis. Women who exercised did not lose significantly more weight than women in the usual care group (two trials; n = 53; MD -0.10 kg; 95% confidence interval (CI) -1.90 to 1.71). Women who took part in a diet (one trial; n = 45; MD -1.70 kg; 95% CI -2.08 to -1.32), or diet plus exercise programme (seven trials; n = 573; MD -1.93 kg; 95% CI -2.96 to -0.89; random-effects, T2 = 1.09, I2 = 71%), lost significantly more weight than women in the usual care group. There was no difference in the magnitude of weight loss between diet alone and diet plus exercise group (one trial; n = 43; MD 0.30 kg; 95% CI -0.06 to 0.66). The interventions seemed not to affect breastfeeding performance adversely. Evidence from this review suggests that both diet and exercise together and diet alone help women to lose weight after childbirth. Nevertheless, it may be preferable to lose weight through a combination of diet and exercise as this improves maternal cardiorespiratory fitness and preserves fat-free mass, while diet alone reduces fat-free mass. This needs confirmation in large trials of high methodological quality. For women who are breastfeeding, more evidence is required to confirm whether diet or exercise, or both, is not detrimental for either mother or baby.


Hosseini M.,Copenhagen University
European journal of oral implantology | Year: 2011

To compare the biological, technical and aesthetic outcomes of single implant-supported all-ceramic versus metal-ceramic crowns. Thirty-six patients with premolar agenesis were randomly treated with 38 all-ceramic (AC) and 37 metal-ceramic (MC) implant-supported single-tooth restorations. A quasi-randomisation of consecutively included restorations in patients with one or more implants was used, i.e. a combination of parallel group (for 13 patients with one restoration) and split-mouth (for 23 patients with ≥2 restorations). All patients were recalled for baseline and 1-year followup examinations. Biological and technical outcomes, including complications, were clinically and radiographically registered. The Copenhagen Index Score and visual analogue scale (VAS) score were used to assess professional and patient-reported aesthetic outcomes, respectively, by blinded assessors. One-year after loading, no patient dropped out and no implant failed, though one MC restoration had to be remade. The marginal bone loss was not significantly different between AC and MC restorations (AC: mean 0.08 mm, SD 0.25; MC: mean 0.10 mm, SD 0.17). Seven out of 10 inflammatory reactions were registered at AC restorations. Two technical complications, one loss of retention and one chipping of veneering porcelain were recorded at two metal-ceramic crowns. The marginal adaptation of the all-ceramic crowns was significantly less optimal than the metal-ceramic crowns (P = 0.014). The professional-reported colour match of all-ceramic crowns was significantly better than metal-ceramic crowns (P = 0.031), but other aesthetic parameters as well as the VAS scores demonstrated no statistically significant difference between AC and MC restorations. Marginal bone loss and the aesthetic outcomes were not significantly different between AC and MC restorations in this short-term follow-up study, though inflammatory reactions in the peri-implant mucosa as well as less optimal marginal adaptation were more frequently registered for all-ceramic compared to the metal-ceramic crowns.


Penninga L.,Copenhagen University
The Cochrane database of systematic reviews | Year: 2013

Lung transplantation is a well-accepted treatment for people with most end-stage lung diseases. Although both tacrolimus and cyclosporin are used as primary immunosuppressive agents in lung transplant recipients, it is unclear which of these drugs is better in reducing rejection and death without causing adverse effects. To assess the benefits and harms of tacrolimus versus cyclosporin for primary immunosuppression in lung transplant recipients. We searched the Cochrane Renal Group's Specialised Register to 10 April 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. We also searched Science Citation Index Expanded and the Transplant Library to 20 April 2013. We included all randomised controlled trials (RCT) that compared any dose and duration of administration of tacrolimus versus cyclosporin as primary immunosuppressive treatment in lung transplant recipients. Our selection criteria required that all included patients received the same additional immunosuppressive therapy within each study. Three authors extracted data. For dichotomous data we used risk ratio (RR) and used mean difference (MD) for continuous data, each with 95% confidence intervals (CI). Methodological components of the included studies were used to assess risk of systematic errors (bias). Trial sequential analysis was used to assess risk of random errors (play of chance). We included three studies that enrolled a total of 413 adult patients that compared tacrolimus with microemulsion or oral solution cyclosporin. All studies were found to be at high risk of bias. Tacrolimus seemed to be significantly superior to cyclosporin regarding the incidence of bronchiolitis obliterans syndrome (RR 0.46, 95% CI 0.29 to 0.74), lymphocytic bronchitis score (MD -0.60, 95% CI -1.04 to -0.16), treatment withdrawal (RR 0.27, 95% CI 0.16 to 0.46), and arterial hypertension (RR 0.67, 95% CI 0.50 to 0.89). However, the finding for arterial hypertension was not confirmed when analysed using a random-effects model (RR 0.54, 95% CI 0.17 to 1.73). Furthermore, trial sequential analysis found that none of the meta-analyses reached the required information sizes and cumulative Z-curves did not cross trial sequential monitoring boundaries. Diabetes mellitus occurred more frequently among people in the tacrolimus group compared with the cyclosporin group when the fixed-effect model was applied (RR 4.24, 95% CI 1.58 to 11.40), but no difference was found when the random-effects model was used for analysis (RR 4.43, 95% CI 0.75 to 26.05). Again, trial sequential analysis found that the required information threshold was not reached and cumulative Z-curve did not cross the trial sequential monitoring boundary. No significant difference between treatment groups was observed regarding mortality (RR 1.06, 95% CI 0.75 to 1.49), incidence of acute rejection (RR 0.89, 95% CI 0.77 to 1.03), numbers of infections/100 patient-days (MD -0.15, 95% CI -0.30 to 0.00), cancer (RR 0.21, 95% CI 0.04 to 1.16), kidney dysfunction (RR 1.41, 95% CI 0.93 to 2.14), kidney failure (RR 1.57, 95% CI 0.28 to 8.94), neurotoxicity (RR 7.06, 95% CI 0.37 to 135.19), and hyperlipidaemia (RR 0.60, 95% CI 0.30 to 1.20). Trial sequential analysis showed the required information thresholds were not reached for any of these outcome measures. Tacrolimus may be superior to cyclosporin regarding bronchiolitis obliterans syndrome, lymphocytic bronchitis, treatment withdrawal, and arterial hypertension, but may be inferior regarding development of diabetes. No difference in mortality and acute rejection was observed between patients treated with tacrolimus and cyclosporin. There were few studies comparing tacrolimus and cyclosporin after lung transplantation, and the numbers of patients and events in the included studies were limited. Furthermore, the included studies were deemed to be at high risk of bias. Hence, more RCTs are needed to assess the results of the present review. Such studies ought to be conducted with low risks of systematic errors (bias) and of random errors (play of chance).


Weinhold N.,Sloan Kettering Cancer Center | Jacobsen A.,Sloan Kettering Cancer Center | Jacobsen A.,Copenhagen University | Schultz N.,Sloan Kettering Cancer Center | And 2 more authors.
Nature Genetics | Year: 2014

Cancer primarily develops because of somatic alterations in the genome. Advances in sequencing have enabled large-scale sequencing studies across many tumor types, emphasizing the discovery of alterations in protein-coding genes. However, the protein-coding exome comprises less than 2% of the human genome. Here we analyze the complete genome sequences of 863 human tumors from The Cancer Genome Atlas and other sources to systematically identify noncoding regions that are recurrently mutated in cancer. We use new frequency- and sequence-based approaches to comprehensively scan the genome for noncoding mutations with potential regulatory impact. These methods identify recurrent mutations in regulatory elements upstream of PLEKHS1, WDR74 and SDHD, as well as previously identified mutations in the TERT promoter. SDHD promoter mutations are frequent in melanoma and are associated with reduced gene expression and poor prognosis. The non-protein-coding cancer genome remains widely unexplored, and our findings represent a step toward targeting the entire genome for clinical purposes. © 2014 Nature America, Inc. All rights reserved.


Vogelius I.R.,Copenhagen University | Bentzen S.M.,University of Wisconsin - Madison
International Journal of Radiation Oncology Biology Physics | Year: 2013

Purpose: To present a novel method for meta-analysis of the fractionation sensitivity of tumors as applied to prostate cancer in the presence of an overall time factor. Methods and Materials: A systematic search for radiation dose-fractionation trials in prostate cancer was performed using PubMed and by manual search. Published trials comparing standard fractionated external beam radiation therapy with alternative fractionation were eligible. For each trial the α/β ratio and its 95% confidence interval (CI) were extracted, and the data were synthesized with each study weighted by the inverse variance. An overall time factor was included in the analysis, and its influence on α/β was investigated. Results: Five studies involving 1965 patients were included in the meta-analysis of α/β. The synthesized α/β assuming no effect of overall treatment time was -0.07 Gy (95% CI -0.73-0.59), which was increased to 0.47 Gy (95% CI -0.55-1.50) if a single highly weighted study was excluded. In a separate analysis, 2 studies based on 10,808 patients in total allowed extraction of a synthesized estimate of a time factor of 0.31 Gy/d (95% CI 0.20-0.42). The time factor increased the α/β estimate to 0.58 Gy (95% CI -0.53-1.69)/1.93 Gy (95% CI -0.27-4.14) with/without the heavily weighted study. An analysis of the uncertainty of the α/β estimate showed a loss of information when the hypofractionated arm was underdosed compared with the normo-fractionated arm. Conclusions: The current external beam fractionation studies are consistent with a very low α/β ratio for prostate cancer, although the CIs include α/β ratios up to 4.14 Gy in the presence of a time factor. Details of the dose fractionation in the 2 trial arms have critical influence on the information that can be extracted from a study. Studies with unfortunate designs will supply little or no information about α/β regardless of the number of subjects enrolled. © 2013 Elsevier Inc.


Dreyer J.K.,Copenhagen University
Journal of Neuroscience | Year: 2014

Progressive loss of nigrostriatal dopamine (DA) neurons is the neuropathological hallmark of Parkinson's disease (PD). Symptoms of the disease can often be treated by DA D2 agonists and thus seem related to disinhibition of the indirect striatal pathway. However, there is no evidence that symptoms arise by low extracellular DA concentration or are associated with reduced D2 receptor binding. Here I provide a theoretical analysis of the pathophysiology and postsynaptic adaptation resulting from striatal DA denervation. I found that progressive denervation may alter DA signaling by three independent mechanisms depending on degree of denervation and macroscopic morphology of the lesion. As long as the remaining innervation stays anatomically coherent, denervation reduces phasic variations in extracellular DA, but the DA tone is not changed. The reduction of phasic signaling can be partially compensated by upregulating postsynaptic signaling cascades. However, changes in DA dynamics evade compensation. With 80–99% denervation, a persistent aberrant signal develops in D2-regulated pathways caused by random fluctuations in tonic DA release. Permanent low DA levels occur in regions completely void of innervation. Simulation of L-dopa therapy reduced the aberrant D2 signal. With a high degree of denervation, L-dopa enhanced another aberrant signal, this time in the D1 pathway. This analysis provides a quantitative, physiologically consistent view of the early and late stages of PD, the effect of main therapeutic medications, and potential side effects. The mechanisms described here may also provide an explanation to currently inexplicable pathological phenomena such as psycho stimulant-induced contraversive rotations in animal models. © 2014 by the Society for Neuroscience. All rights reserved.


Kliebenstein D.J.,University of California at Davis | Kliebenstein D.J.,Copenhagen University
Trends in Plant Science | Year: 2014

Research over the past decades has made immense progress in identifying some genes and mechanisms underlying plant defense against biotic organisms. The recent movement towards systems biology approaches has increased mechanistic knowledge, revealing a need for understanding how all the genes and mechanisms integrate to create a response to any given biotic interaction. This begins with evidence that diverse molecular patterns converge, suggesting that the plant perceives signals not the interacting species. These signals then coordinate across regulatory networks via molecular interactions and cause non-cell autonomous responses in neighboring and systemic cells. Finally, the identification of transporters is showing that plant defenses are harmonized across tissues and even show the potential for coordination across individuals within a population. © 2014 Elsevier Ltd.


Hansen H.S.,Copenhagen University
Pharmacological Research | Year: 2014

Anandamide is a well-known agonist for the cannabinoid receptors. Along with endogenous anandamide other non-endocannabinoid N-acylethanolamines are also formed, apparently in higher amounts. These include mainly oleoylethanolamide (OEA), palmitoyelethanolamide (PEA) and linoleoylethanolamide (LEA), and they have biological activity by themselves being anorectic and anti-inflammatory. It appears that the major effect of dietary fat on the level of these molecules is in the gastrointestinal system, where OEA, PEA and LEA in the enterocytes may function as homeostatic signals, which are decreased by prolonged consumption of a high-fat diet. These lipid amides appear to mediate their signaling activity via activation of PPARα in the enterocyte followed by activation of afferent vagal fibers leading to the brain. Through this mechanism OEA, PEA and LEA may both reduce the consumption of a meal as well as increase the reward value of the food. Thus, they may function as homeostatic intestinal signals involving hedonic aspects that contribute to the regulation of the amounts of dietary fat to be ingested. © 2014 Elsevier Ltd.


Wulff-Nilsen C.,Copenhagen University
Proceedings of the Annual ACM-SIAM Symposium on Discrete Algorithms | Year: 2010

In a graph G with non-negative edge lengths, let P be a shortest path from a vertex s to a vertex t. We consider the problem of computing, for each edge e on P, the length of a shortest path in G from s to t that avoids e. This is known as the replacement paths problem. We give a linear-space algorithm with O(n log n) running time for n-vertex planar directed graphs. The previous best time bound was O(n log2 n). Copyright © by SIAM.


Burnstock G.,University College London | Novak I.,Copenhagen University
Journal of Endocrinology | Year: 2012

Pancreatic cells contain specialised stores for ATP. Purinergic receptors (P2 and P1) and ecto-nucleotidases are expressed in both endocrine and exocrine calls, as well as in stromal cells. The pancreas, especially the endocrine cells, were an early target for the actions of ATP. After the historical perspective of purinergic signalling in the pancreas, the focus of this review will be the physiological functions of purinergic signalling in the regulation of both endocrine and exocrine pancreas. Next, we will consider possible interaction between purinergic signalling and other regulatory systems and their relation to nutrient homeostasis and cell survival. The pancreas is an organ exhibiting several serious diseases - cystic fibrosis, pancreatitis, pancreatic cancer and diabetes - and some are associated with changes in life-style and are increasing in incidence. There is upcoming evidence for the role of purinergic signalling in the pathophysiology of the pancreas, and the new challenge is to understand how it is integrated with other pathological processes. © 2012 Society for Endocrinology.


Background The cyanobacterial genus Nostoc includes several species forming centimetre-large gelatinous colonies in nutrient-poor freshwaters and harsh semi-terrestrial environments with extended drought or freezing. These Nostoc species have filaments with normal photosynthetic cells and N2-fixing heterocysts embedded in an extensive gelatinous matrix of polysaccharides and many other organic substances providing biological and environmental protection. Large colony size imposes constraints on the use of external resources and the gelatinous matrix represents extra costs and reduced growth rates. Scope The objective of this review is to evaluate the mechanisms behind the low rates of growth and mortality, protection against environmental hazards and the persistence and longevity of gelatinous Nostoc colonies, and their ability to economize with highly limiting resources. Conclusions Simple models predict the decline in uptake of dissolved inorganic carbon (DIC) and a decline in the growth rate of spherical freshwater colonies of N. pruniforme and N. zetterstedtii and sheet-like colonies of N. commune in response to a thicker diffusion boundary layer, lower external DIC concentration and higher organic carbon mass per surface area (CMA) of the colony. Measured growth rates of N. commune and N. pruniforme at high DIC availability comply with general empirical predictions of maximum growth rate (i.e. doubling time 10-14 d) as functions of CMA for marine macroalgae and as functions of tissue thickness for aquatic and terrestrial plants, while extremely low growth rates of N. zetterstedtii (i.e. doubling time 2-3 years) are 10-fold lower than model predictions, either because of very low ambient DIC and/or an extremely costly colony matrix. DIC uptake is limited by diffusion at low concentrations for all species, although they exhibit efficient HCO3 - uptake, accumulation of respiratory DIC within the colonies and very low CO2 compensation points. Long light paths and light attenuation by structural substances in large Nostoc colonies cause lower quantum efficiency and assimilation number and higher light compensation points than in unicells and other aquatic macrophytes. Extremely low growth and mortality rates of N. zetterstedtii reflect stress-selected adaptation to nutrient- and DIC-poor temperate lakes, while N. pruniforme exhibits a mixed ruderal- and stress-selected strategy with slow growth and year-long survival prevailing in sub-Arctic lakes and faster growth and shorter longevity in temperate lakes. Nostoc commune and its close relative N. flagelliforme have a mixed stress-disturbance strategy not found among higher plants, with stress selection to limiting water and nutrients and disturbance selection in quiescent dry or frozen stages. Despite profound ecological differences between species, active growth of temperate specimens is mostly restricted to the same temperature range (0-35 °C; maximum at 25 °C). Future studies should aim to unravel the processes behind the extreme persistence and low metabolism of Nostoc species under ambient resource supply on sediment and soil surfaces. © 2014 The Author 2014.


Hansen S.,Copenhagen University
Journal of Applied Crystallography | Year: 2012

A web site (http://www.bayesapp.org) for indirect transformation of small-angle scattering data is presented. When experimental data are uploaded to the server, they are processed in a few seconds and the result of the indirect information is displayed on the screen in the form of a distribution, together with the experimental data and the fit to the data. No other user input than the experimental data is necessary, but various options for the analysis may be selected. The results of the analysis can be downloaded from the web site in the form of ASCII files. © 2012 International Union of Crystallography Printed in Singapore-all rights reserved.


Objective: To investigate the influence of timing of hard palate closure on early speech development from 18 months to 3 years of age. Design: A prospective, randomized clinical trial. Participants: Thirty-four children with unilateral cleft lip and palate (UCLP) with velum closure at 4 months of age, and hard palate closure at 12 months (early hard palate repair, EarlyHPR) or 36 months (late hard palate unrepaired, LateHPU) by random assignment. Thirty-five control children were matched for gender and age. Methods: All children were video recorded during a play interaction with a parent at 18 months of age. These recordings were transcribed according to the International Phonetic Alphabet. At 36 months a single word naming test was administered. Results: At 18 months the LateHPU group produced fewer labial stops and more velar stops than the EarlyHPR group. Unlike the EarlyHPR group, the LateHPU group produced fewer vocalizations, consonants, and consonants permissible in word-initial position than the control group. Additionally, both cleft palate groups had a smaller productive vocabulary than the control group, but unlike the EarlyHPR group, the LateHPU group produced a smaller number of word tokens in social interaction than the control group. By 3 years of age, the LateHPU group had a (severely) restricted phonological system and produced more cleft speech characteristics than the EarlyHPR group. Conclusions: Surgical timing of hard palate repair in a two-stage procedure appears to have an influence on early speech development in children with cleft palate. © Copyright 2012 American Cleft Palate-Craniofacial Association.


Pedersen D.S.,Copenhagen University | Abell A.,University of Adelaide
European Journal of Organic Chemistry | Year: 2011

The ability to synthesise small peptidomimetics that mimic the secondary structure of proteins is an ever expanding area of research directed at sourcing new medicinal agents and biological probes. A significant current challenge is to mimic protein epitopes under physiological conditions using small peptidomimetics that are easy to prepare. The copper- and ruthenium-catalysed Huisgen cycloaddition reactions provide such a general synthetic method, with the resulting 1,2,3-triazoles being good peptide bond mimics. The ability to prepare both 1,4- and 1,5-substituted 1,2,3-triazoles under these chemically benign conditions provides both "linear" and "bent" peptidomimetics. Examples of the use of 1,2,3-triazoles to define the geometry and properties of a peptidomimetic abound. This review highlights such successes but also describes a number of failures in order to guide and inspire future efforts of chemists in this area. The incorporation of 1,4- and 1,5-substituted 1,2,3-triazoles in peptidomimetics enables both shape and function to be controlled by covalent or non-covalent interactions. The approach has many applicationsin the synthesis of, for example, natural product analogues, turn structures and α-helical architectures that have been shown to retain their shape and function in aqueous solution. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Sorensen C.S.,Copenhagen University | Syljuasen R.G.,University of Oslo
Nucleic Acids Research | Year: 2012

Mechanisms that preserve genome integrity are highly important during the normal life cycle of human cells. Loss of genome protective mechanisms can lead to the development of diseases such as cancer. Checkpoint kinases function in the cellular surveillance pathways that help cells to cope with DNA damage. Importantly, the checkpoint kinases ATR, CHK1 and WEE1 are not only activated in response to exogenous DNA damaging agents, but are active during normal S phase progression. Here, we review recent evidence that these checkpoint kinases are critical to avoid deleterious DNA breakage during DNA replication in normal, unperturbed cell cycle. Possible mechanisms how loss of these checkpoint kinases may cause DNA damage in S phase are discussed. We propose that the majority of DNA damage is induced as a consequence of deregulated CDK activity that forces unscheduled initiation of DNA replication. This could generate structures that are cleaved by DNA endonucleases leading to the formation of DNA double-strand breaks. Finally, we discuss how these S phase effects may impact on our understanding of cancer development following disruption of these checkpoint kinases, as well as on the potential of these kinases as targets for cancer treatment. © The Author(s) 2011. Published by Oxford University Press.


Jemec G.B.E.,Roskilde Hospital | Jemec G.B.E.,Copenhagen University
New England Journal of Medicine | Year: 2012

A 36-year-old woman has recurrent boils under both arms and in the groin. They flare premenstrually, causing pain, suppuration, and an offensive odor. Scarring has developed in the groin area, and chronically draining sinus tracts are interspersed with normal skin. Treatment with short courses of antibiotics or with incision and drainage has had no apparent effect, and she has become socially isolated because of embarrassment about her condition. How would you manage this case? Copyright © 2012 Massachusetts Medical Society. All rights reserved.


Specific inhibition of the cytokine, tumor necrosis factor-a (TNF), has revolutionized the treatment of patients with several autoimmune diseases, and genetically engineered anti-TNF antibody constructs now constitute a heavy medicinal expenditure in many countries. Unfortunately, up to 30% of patients do not respond and about 50% of those who do loose response with time. Furthermore, safety may be compromised by immunogenicity with the induction of anti-drug-antibodies (ADA). Assessment of drug pharmacokinetics and ADA is increasingly recognized as a requirement for safe and rational use of protein drugs. The use of therapeutic strategies based on anti-TNF drug levels and ADA rather than dose-escalation has also proven to be cost-effective, as this allows individualized patient-tailored strategies rather than the current universal approach to loss of response. The objective of the present article - and the accompanying article - is to discuss the reasons for recommending assessments of circulating drug and ADA levels in patients treated with anti-TNF biopharmaceuticals and to detail some of the methodological issues that obscure cost-effective and safer therapies. © 2015 Bendtzen.


Dossing A.,Copenhagen University
Coordination Chemistry Reviews | Year: 2014

A review of the advances since 1988 of the chemistry of hydroxo-bridged chromium(III) complexes will be presented. The structures of novel hydroxo- and oxo-bridged complexes will be described along with their optical and magnetic properties. The thermodynamics and kinetics of hydroxo bridge formation and cleavage and of other reactions will be discussed. The results of theoretical calculations of the optical and magnetic properties of the complexes are included. © 2014 Elsevier B.V.


Background: Quantification of Hepatitis C Virus (HCV)-RNA is important for the clinical management of patients undergoing antiviral therapy. Objectives: To compare the quantification of clinical plasma samples by the Roche COBAS AmpliPrep/COBAS TaqMan HCV test v2.0 and the artus HCV QS-RGQ test. Study design: HCV-RNA viral load in 155 plasma samples from HCV-seropositive individuals was determined using the COBAS test and retrospectively with the artus. Furthermore, a dilution series of an Acrometrix standard was tested with both tests in replicates of five to assess differences in limit of detection and precision. Results: Two clinical samples showed inhibition using the artus test and were excluded from analysis. Of the clinical samples, 20 tested negative in both tests, 7 tested positive in the COBAS test and negative in the artus test, and 126 samples were quantified by both tests. The mean overall difference between tests (artus-COBAS) was 0.27. log. IU/mL. The mean difference of quantification varied little across genotype 1a, 1b, 2b and 3a (range: +0.15 to +0.35. log. IU/mL). Both tests were precise (%CV at 1000. IU/mL 1.1 and 1.8 for the COBAS and artus test, respectively). Conclusions: The limit of detection appeared lower in the COBAS test than the artus test when analyzed from a limited number of replicates. Both tests were precise with the artus test quantifying higher than the COBAS test on average. It is therefore recommended to monitor individual patients with the same test throughout treatment. © 2014 Elsevier B.V.


Haynes L.,Trudeau Institute | Parker C.,Academic Urology Unit | Iversen P.,Copenhagen University
Journal of the National Cancer Institute | Year: 2012

Sipuleucel-T was approved by the US Food and Drug Administration on April 29, 2010, as an immunotherapy for late-stage prostate cancer. To manufacture sipuleucel-T, mononuclear cells harvested from the patient are incubated with a recombinant prostatic acid phosphatase (PAP) antigen and reinfused. The manufacturer proposes that antigen-presenting cells exogenously activated by PAP induce endogenous T-cells to attack PAP-bearing prostate cancer cells. However, the lack of demonstrable tumor responses has prompted calls for scrutiny of the design of the trials in which sipuleucel-T demonstrated a 4-month survival benefit. Previously unpublished data from the sipuleucel-T trials show worse overall survival in older vs younger patients in the placebo groups, which have not been shown previously to be prognostic for survival in castration-resistant prostate cancer patients receiving chemotherapy. Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival "benefit." Patient safety depends on adequately addressing this alternative explanation for the trial results. © 2012 The Author (s). Published by Oxford University Press.


Lenhard B.,Imperial College London | Lenhard B.,Clinical Science Center | Lenhard B.,University of Bergen | Sandelin A.,Copenhagen University | Carninci P.,RIKEN
Nature Reviews Genetics | Year: 2012

Promoters are crucial for gene regulation. They vary greatly in terms of associated regulatory elements, sequence motifs, the choice of transcription start sites and other features. Several technologies that harness next-generation sequencing have enabled recent advances in identifying promoters and their features, helping researchers who are investigating functional categories of promoters and their modes of regulation. Additional features of promoters that are being characterized include types of histone modifications, nucleosome positioning, RNA polymerase pausing and novel small RNAs. In this Review, we discuss recent findings relating to metazoan promoters and how these findings are leading to a revised picture of what a gene promoter is and how it works. © 2012 Macmillan Publishers Limited. All rights reserved.


Loland C.J.,Copenhagen University
Biochimica et Biophysica Acta - General Subjects | Year: 2015

Background The mammalian neurotransmitter transporters are complex proteins playing a central role in synaptic transmission between neurons by rapid reuptake of neurotransmitters. The proteins which transport dopamine, noradrenaline and serotonin belong to the Neurotransmitter:Sodium Symporters (NSS). Due to their important role, dysfunctions are associated with several psychiatric and neurological diseases and they also serve as targets for a wide range of therapeutic and illicit drugs. Despite the central physiological and pharmacological importance, direct evidence on structure-function relationships on mammalian NSS proteins has so far been unsuccessful. The crystal structure of the bacterial NSS protein, LeuT, has been a turning point in structural investigations. Scope of review To provide an update on what is known about the binding sites for substrates and inhibitors in the LeuT. The different binding modes and binding sites will be discussed with special emphasis on the possible existence of a second substrate binding site. It is the goal to give an insight into how investigations on ligand binding in LeuT have provided basic knowledge about transporter conformations and translocation mechanism which can pave the road for a deeper understanding of drug binding and function of the mammalian transporters. Major conclusions The LeuT is a suitable model for the structural investigation of NSS proteins including the possible location of drug binding sites. It is still debated whether the LeuT is a suitable model for the molecular mechanisms behind substrate translocation. General significance Structure and functional aspects of NSS proteins are central for understanding synaptic transmission. With the purification and crystallization of LeuT as well as the dopamine transporter from Drosophila melanogaster, the application of biophysical methods such as fluorescence spectroscopy, neutron- or x-ray scattering and NMR for understanding its function becomes increasingly available. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins. © 2014 Elsevier B.V. All rights reserved.


Saxe H.,Copenhagen University
American Journal of Clinical Nutrition | Year: 2014

Background: The New Nordic Diet (NND) was designed by gastronomic, nutritional, and environmental specialists to be a palatable, healthy, and sustainable diet containing 35% less meat than the Average Danish Diet (ADD); more whole-grain products, nuts, fruit, and vegetables; locally grown food in season; and >75% organic produce. The environmental impact of the 2 diets was compared based on 16 impact categories, which were monetized to evaluate the overall socioeconomic effect of a shift from an ADD to an NND. Objective: The objective was to determine whether this diet shift can be an effective tool in environmental protection. Design: The 3 features by which this diet shift affects the environment-composition, transport (import), and type of production (organic/conventional)-were separately investigated by using life cycle assessment. Results: When both diet composition and transport were taken into account, the NND reduced the environmental impact relative to the ADD measured by all 16 impact categories. The socioeconomic savings related to this diet shift was €266/person per year, or 32% of the overall environmental cost of the ADD. When the actual 8% content of organic produce in the ADD and the 84% content of organic produce in the investigated recipe-based NND were also taken into account, the NND reduced the environmental impact relative to the ADD measured by only 10 of the 16 impact categories whereas 6 were increased. The socioeconomic savings related to the diet shift were lowered to €42/person per year, or 5% of the overall environmental cost of the ADD. Conclusion: Reducing the content of meat and excluding most longdistance imports were of substantial environmental and socioeconomic advantage to the NND when compared with the ADD, whereas including high amounts of organic produce was a disadvantage. © 2014 American Society for Nutrition.


Dissipative particle dynamics simulations are used to investigate the self-assembly of A(BC)2 3-mikto-arm star copolymers. The simulations predict a range of structures obtained by varying the volume fractions of the 3 components. Most notably the simulations show that a 3-colored perforated lamellar phase recently identified experimentally where the C and B components perforate lamellae of A is stable over a wide range of compositions. Further, the possibility of forming two other completely novel morphologies in this system is highlighted, one consisting of spheres of the A component and a 3-connected gyroid-like network of the C component embedded in a matrix of B and the other consisting of a single core-shell 3-connected gyroid-like network of A wrapped with B and embedded in a matrix of C. If realized experimentally, these networks potentially represent chiral structures built from achiral molecules as well as a single network analogue of an ordinary bicontinuous structure. © 2010 The Royal Society of Chemistry.


Sauer S.P.A.,Copenhagen University
Journal of Chemical Physics | Year: 2010

The rotational g -factor and spin-rotation constants of the methylidynium ion CH+ have been calculated for the first time with a large multiconfigurational self-consistent field wave function and at the coupled-cluster singles and doubles level augmented by a perturbative triples correction. The results for an equilibrium internuclear distance as well as for the v=0, J=1 vibration-rotational state are presented. © 2010 American Institute of Physics.


Sorensen M.V.,Copenhagen University
Zootaxa | Year: 2013

The phylum Kinorhyncha includes 196 described species, distributed on 21 (soon 22) genera, and nine families. Two genera are currently not assigned to any family. The families are distributed on two orders, Cyclorhagida and Homalorhagida. Currently, kinorhynch classification does not reflect actual relationships revealed as a result of numerical phylogenetic analyses, but such studies are currently being carried out, and a revision of the kinorhynch classification is expected within a short time. Copyright © 2013 Magnolia Press.


The sediment budget along the southern part of the exposed Danish North Sea coast was assessed through a combination of cross-shore profile analysis, numerical modeling and field measurements of cross-shore and longshore sediment transport at the boundary between the upper and the lower shorefaces. The beaches along this coast are accreting but observed sediment storage is far smaller than sediment supplied by southerly directed wave-driven currents. The excess sediment volumes are transferred seaward across the shoreface by systematically offshore-migrating nearshore bars that deliver sediment to the lower shoreface from where it is eventually removed by northward-directed wind-generated currents. In the geological past, sediment storage rates were much larger than at present and it is likely that the rate of storage along this coastline decreased as shoreface geometry adjusted towards equilibrium associated with shoreface steepening. © 2011 Elsevier B.V.


Jonsson K.A.,Copenhagen University
BMC evolutionary biology | Year: 2012

Crows and ravens (Passeriformes: Corvus) are large-brained birds with enhanced cognitive abilities relative to other birds. They are among the few non-hominid organisms on Earth to be considered intelligent and well-known examples exist of several crow species having evolved innovative strategies and even use of tools in their search for food. The 40 Corvus species have also been successful dispersers and are distributed on most continents and in remote archipelagos. This study presents the first molecular phylogeny including all species and a number of subspecies within the genus Corvus. We date the phylogeny and determine ancestral areas to investigate historical biogeographical patterns of the crows. Additionally, we use data on brain size and a large database on innovative behaviour and tool use to test whether brain size (i) explains innovative behaviour and success in applying tools when foraging and (ii) has some correlative role in the success of colonization of islands. Our results demonstrate that crows originated in the Palaearctic in the Miocene from where they dispersed to North America and the Caribbean, Africa and Australasia. We find that relative brain size alone does not explain tool use, innovative feeding strategies and dispersal success within crows. Our study supports monophyly of the genus Corvus and further demonstrates the direction and timing of colonization from the area of origin in the Palaearctic to other continents and archipelagos. The Caribbean was probably colonized from North America, although some North American ancestor may have gone extinct, and the Pacific was colonized multiple times from Asia and Australia. We did not find a correlation between relative brain size, tool use, innovative feeding strategies and dispersal success. Hence, we propose that all crows and ravens have relatively large brains compared to other birds and thus the potential to be innovative if conditions and circumstances are right.


Linnet K.,Copenhagen University
Journal of Forensic and Legal Medicine | Year: 2012

In postmortem toxicology, it is important to know what the usual drug level is in blood under ordinary therapy to make correct interpretations with regard to the possible occurrence of poisoning. A commonly used source is The International Association of Forensic Toxicologists (TIAFT) list of drug concentrations providing therapeutic drug levels, usually measured in serum. In this article, published postmortem-derived blood drug reference concentration intervals were related to therapeutic serum levels of drugs from the TIAFT list to assess agreement or discrepancies with focus on the importance of postmortem redistribution. The ratio between the upper limits was evaluated. This ratio ranged from 0.13 to 11.3 for 57 compounds with a median value of 1.5. For about a third of the compounds the ratio exceeded three. There was a tendency that for highly water-soluble drugs with a low propensity for redistribution, the ratio was generally low. For example, for pentobarbital, carisoprodol, meprobamate, carbamazepine, phenazone and theophylline, the ratio ranged from 0.14 to 1.1 with a median of 0.4. For the 15 antidepressants considered, on the other hand, the ratio was relatively high, ranging from 0.6 to 4.7 (median 2.4). For antipsychotics, the ratio ranged from 0.2 to 11.3 with a median of 1.4. In conclusion, there were generally wide discrepancies between serum-based intervals as presented in the TIAFT list and published postmortem blood-based drug reference intervals. More focus on postmortem-derived intervals is encouraged, so that those that have been estimated are cited in reference publications and so that further intervals are estimated. Ultimately, a reliable database of postmortem blood-based drug reference intervals for use by the forensic community is desirable. © 2012 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.


Springborg L.K.,Copenhagen University
European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery | Year: 2013

In transcervical resection of the submandibular gland for benign lesions, only a limited risk of damage to neural structures can be accepted and a cosmetically satisfactory result is mandatory. In this retrospective case series, we evaluated 139 patients operated over a 10-year period and completed long-term clinical follow-up of 113 of these patients after a median of 81 months. In all patients, the operation was effective. We found a 4.3 % risk of reoperation for wound infection or postoperative hematomas and an 18.7 % risk of early paresis of the marginal branch of the facial nerve, which decreased to 2.7 % on long-term follow-up. We found a 4.4 % risk of permanent lingual nerve paresis, and no patients had damage to the hypoglossal nerve. Xerostomia was found in 22.1 % of the patients and could be quantified by the easily performed biscuit test. Only 2.5 % reported an unsatisfactory cosmetic result and all scars were ≤ 6 on the Vancouver Scar Scale. Problems with scarring were more common if there had been postoperative infection. We continue to use the lateral transcervical approach as standard in our institution for patients who cannot be managed by gland-sparing procedures.


Nielsen C.,Copenhagen University
Journal of Experimental Biology | Year: 2015

The apical organ of ciliated larvae of cnidarians and bilaterians is a true larval organ that disappears before or at metamorphosis. It appears to be sensory, probably involved in metamorphosis, but knowledge is scant. The ciliated protostome larvae show ganglia/nerve cords that are retained as the adult central nervous system (CNS). Two structures can be recognized, viz. a pair of cerebral ganglia, which form the major part of the adult brain, and a blastoporal (circumblastoporal) nerve cord, which becomes differentiated into a perioral loop, paired or secondarily fused ventral nerve cords and a small perianal loop. The anterior loop becomes part of the brain. This has been well documented through cell-lineage studies in a number of spiralians, and homologies with similar structures in the ecdysozoans are strongly indicated. The deuterostomes are generally difficult to interpret, and the nervous systems of echinoderms and enteropneusts appear completely enigmatic. The ontogeny of the chordate CNS can perhaps be interpreted as a variation of the ontogeny of the blastoporal nerve cord of the protostomes, and this is strongly supported by patterns of gene expression. The presence of 'deuterostomian' blastopore fates both in an annelid and in a mollusk, which are both placed in families with the 'normal' spiralian gastrulation type, and in the chaetognaths demonstrates that the chordate type of gastrulation could easily have evolved from the spiralian type. This indicates that the latest common ancestor of the deuterostomes was very similar to the latest common pelago-benthic ancestor of the protostomes as described by the trochaea theory, and that the neural tube of the chordates is morphologically ventral. © 2015. Published by The Company of Biologists Ltd.


Kumakura Y.,Copenhagen University
PloS one | Year: 2013

A previous study of the DOPA decarboxylase substrate 6-[(18)F]fluoro-L-DOPA (FDOPA) with positron emission tomography (PET) detected no difference of the net blood-brain transfer rate (Kin(app)) between detoxified alcoholic patients and healthy controls. Instead, the study revealed an inverse correlation between Kin (app) in left ventral striatum and alcohol craving scores. To resolve the influx and efflux phases of radiolabeled molecules, we independently estimated the unidirectional blood-brain FDOPA clearance rate (K) and the washout rate of [(18)F]fluorodopamine and its deaminated metabolites (k(loss)), and we also calculated the total distribution volume of decarboxylated metabolites and unmetabolized FDOPA as a steady-state index of the dopamine storage capacity (V(d)) in brain. The craving scores in the 12 alcoholics correlated positively with the rate of loss (k(loss)) in the left ventral striatum. We conclude that craving is most pronounced in the individuals with relatively rapid dopamine turnover in the left ventral striatum. The blood-brain clearance rate (K), corrected for subsequent loss of radiolabeled molecules from brain, was completely normal throughout the brain of the alcoholics, in whom the volume of distribution (V(d)) was found to be significantly lower in the left caudate nucleus. The magnitude of Vd in the left caudate head was reduced by 43% relative to the 16 controls, consistent with a 58% increase of k(loss). We interpret the findings as indicating that a trait for rapid dopamine turnover in the ventral striatum subserves craving and reward-dependence, leading to an acquired state of increased dopamine turnover in the dorsal striatum of detoxified alcoholic patients.


Skeletal muscle energy metabolism has been a research focus of physiologists for more than a century. Yet, how the use of intramuscular carbohydrate and lipid energy stores are coordinated during different types of exercise remains a subject of debate. Controversy arises from contradicting data from numerous studies, which used different methodological approaches. Here we review the "pros and cons" of previously used histochemical methods and describe an optimized method to ensure the preservation and specificity of detection of both intramyocellular carbohydrate and lipid stores. For optimal preservation of muscle energy stores, air drying cryosections or cycles of freezing-thawing need to be avoided. Furthermore, optimization of the imaging settings in order to specifically image intracellular lipid droplets stained with oil red O or Bodipy-493/503 is shown. When co-staining lipid droplets with associated proteins, Bodipy-493/503 should be the dye of choice, since oil red O creates precipitates on the lipid droplets blocking the light. In order to increase the specificity of glycogen stain, an antibody against glycogen is used. The resulting method reveals the existence of two metabolically distinct myosin heavy chain I expressing fibers: I-1 fibers have a smaller crossectional area, a higher density of lipid droplets, and a tendency to lower glycogen content compared to I-2 fibers. Type I-2 fibers have similar lipid content than IIA. Exhaustive exercise lead to glycogen depletion in type IIA and IIX fibers, a reduction in lipid droplets density in both type I-1 and I-2 fibers, and a decrease in the size of lipid droplets exclusively in type I-1 fibers.


Penninga L.,Copenhagen University
Cochrane database of systematic reviews (Online) | Year: 2012

The therapeutic success of liver transplantation has been largely attributable to the development of effective immunosuppressive treatment regimens. In particular, calcineurin inhibitors were essential in reducing acute rejection and improving early survival. Currently, more than 90% of all liver transplant recipients are treated with the calcineurin inhibitor cyclosporine or tacrolimus. Unfortunately, calcineurin inhibitors cause adverse events, such as nephrotoxicity, and because of this, minimisation (reduction and withdrawal) regimens of calcineurin inhibitor have been developed and studied. However, the benefits and harms of these minimisation regimens are unclear. To assess the benefits and harms of calcineurin inhibitor minimisation for liver transplant recipients without substitution by another immunosuppressive agent. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2010), Cochrane Central Register of Controlled Clinical Trials (CENTRAL) in The Cochrane Library, MEDLINE (OvidSP), EMBASE (OvidSP), Science Citation Index Expanded (Royle 2003), and the World Health Organization (WHO) international clinical trials registry platform (www.who.int/ictrp) until August 2011. In addition, we searched bibliographies of relevant articles as well as US Food and Drug Administration (FDA) and European Medicines Agency (EMA) drug approval reviews for additional trials. We planned to select all randomised clinical trials investigating calcineurin inhibitor reduction or withdrawal in liver transplant recipients, irrespective of blinding, publication status, or language. Quasi-randomised clinical studies and cohort studies that were obtained through the searches were considered only for the reporting of harms. Trials investigating substitution of one calcineurin inhibitor by another calcineurin inhibitor were excluded. Trials investigating calcineurin inhibitor withdrawal concurrently with switching over to a mammalian target of rapamycin (mTOR) inhibitor-based regimen (everolimus or sirolimus) or mycophenolate mofetil-based regimen are the subject of a separate review. Search strategies were used to obtain titles and abstracts of studies that were relevant for the review. Two authors independently scanned the references and assessed trial eligibility. A total of 1299 references were identified by the searches. After removal of duplicates, 794 references were left. Out of these, two abstract reports of one ongoing randomised trial fulfilled the inclusion criteria of the review. This ongoing trial studies total withdrawal of immunosuppression in patients who receive a calcineurin inhibitor (cyclosporine or tacrolimus) or mycophenolate mofetil as the only immunosuppressive agent. The trial compares withdrawal of calcineurin inhibitor or mycophenolate mofetil with continuation of calcineurin inhibitor or mycophenolate mofetil. However, no trial results on the outcomes of interest to this review were available. This review shows that strategies regarding calcineurin inhibitor minimisation, that is, reduction or withdrawal, without substitution versus continuation of calcineurin inhibitor treatment lack evidence from randomised trials.More research with calcineurin inhibitor reduction and withdrawal regimens is needed to optimise dosing and timing of calcineurin inhibitor treatment in order to achieve optimal patient and graft survival with a minimum of adverse events.Specifically regarding calcineurin inhibitor reduction versus no reduction, we recommend that randomised trials evaluating calcineurin inhibitor reduction versus continuation of calcineurin inhibitor treatment are conducted.Regarding calcineurin inhibitor withdrawal, we recommend that mechanisms for tolerance and 'graft acceptance' are clarified, and patient groups likely to tolerate calcineurin inhibitor withdrawal are identified in order to select the right patients for total withdrawal of calcineurin inhibitors without substitution with another immunosuppressive drug. The randomised trials should only be performed in highly selected patients.


Graudal N.,Copenhagen University
Current Hypertension Reports | Year: 2015

The 2013 Institute of Medicine (IOM) report “Sodium Intake in Populations: Assessment of Evidence” did not support the current recommendations of the IOM and the American Heart Association (AHA) to reduce daily dietary sodium intake to below 2300 mg. The report concluded that the population-based health outcome evidence was not sufficient to define a safe upper intake level for sodium. Recent studies have extended this conclusion to show that a sodium intake below 2300 mg/day is associated with increased mortality. In spite of this increasing body of evidence, the AHA, Centers for Disease Control (CDC), other public health advisory bodies, and major medical journals have continued to support the current policy of reducing dietary sodium. © 2015, Springer Science+Business Media New York.


Contribution of "Women's Gold" to West African Livelihoods: The Case of Shea (Vitellaria paradoxa) in Burkina Faso. This paper (i) quantifies the contribution that Vitellaria paradoxa makes to the total income of rural households belonging to different economic groups in two areas of Burkina Faso; (ii) quantifies the involvement of women in shea nuts and fruits collection and processing; and (iii) empirically verifies the "gap filling" function of shea products in Burkina Faso by quantifying the commercialization and subsistence use of shea fruits, nuts, and butter between agricultural seasons. Based on data collected from structured household surveys used on a quarterly basis during a one-year period on 536 households, we demonstrate that the reliance on shea is generally high in the sampled populations, and is at its highest for the poorest households, for which it contributes 12 % of total household income. Moreover, shea nut collection and processing was found to provide a valuable source of cash income to female household members who otherwise have very few income possibilities. Finally, due to its ecology, shea fills in an income gap during a period where human activities are at their highest while income is at its lowest. Although shea is crucial for poor people's livelihoods and for the generation of income for women, its harvesting and processing are time-consuming activities that generate low returns per unit of labor. We argue that shea collection and processing should therefore not be considered as a remedy to poverty but instead as a way for households to diversify their livelihood strategy and decrease their vulnerability to food insecurity and climate variability. © 2012 The New York Botanical Garden.


Parhamifar L.,Copenhagen University
Methods in molecular biology (Clifton, N.J.) | Year: 2013

Cellular toxicity and/or cell death entail complex mechanisms that require detailed evaluation for proper characterization. A detailed mechanistic assessment of cytotoxicity is essential for design and construction of more effective polycations for nucleic acid delivery. A single toxicity assay cannot stand alone in determining the type and extent of damage or cell death mechanism. In this chapter we describe a lactate dehydrogenase (LDH) assay for high-throughput screening that can be used as a starting point for further detailed cytotoxicity determination. LDH release is considered an early event in necrosis but a late event in apoptosis. An accurate temporal assessment of the toxic responses is crucial as late apoptosis may convert into necrosis as well as in situations where cell death is initiated without any visible cell morphological changes or responses in assays measuring late events, resulting in early ongoing toxicity being overlooked.


Background: Cochrane Reviews are methodologically of high quality but the clinical relevance of analysed efficacy measures (EMs) should also be assessed. Methods: The clinical relevance of EMs used in one systematic Cochrane review of oral zolmitriptan for migraine headache was evaluated. Results: The following EMs were used: pain free at two hours (30%), headache relief at two hours (60%), sustained pain free for 24 hours (19%) and sustained headache relief for 24 hours (39%). These EMs were also used in four other Cochrane reviews of acute migraine treatment. Of these EMs sustained headache relief for 24 h is not judged clinically relevant. Conclusion: Pain free and sustained pain free are clinically relevant, but the responses are rather low, demonstrating that there is a need for improvement of acute drug treatment in migraine. © International Headache Society 2014 Reprints and permissions.


Boomsma J.J.,Copenhagen University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

Obligate eusociality with distinct caste phenotypes has evolved from strictly monogamous sub-social ancestors in ants, some bees, some wasps and some termites. This implies that no lineage reached the most advanced form of social breeding, unless helpers at the nest gained indirect fitness values via siblings that were identical to direct fitness via offspring. The complete lack of re-mating promiscuity equalizes sex-specific variances in reproductive success. Later, evolutionary developments towards multiple queen-mating retained lifetime commitment between sexual partners, but reduced male variance in reproductive success relative to female's, similar to the most advanced vertebrate cooperative breeders. Here, I (i) discuss some of the unique and highly peculiar mating system adaptations of eusocial insects; (ii) address ambiguities that remained after earlier reviews and extend the monogamy logic to the evolution of soldier castes; (iii) evaluate the evidence for indirect fitness benefits driving the dynamics of (in)vertebrate cooperative breeding, while emphasizing the fundamental differences between obligate eusociality and cooperative breeding; (iv) infer that lifetime commitment is a major driver towards higher levels of organization in bodies, colonies and mutualisms. I argue that evolutionary informative definitions of social systems that separate direct and indirect fitness benefits facilitate transparency when testing inclusive fitness theory.


Bombin H.,Perimeter Institute for Theoretical Physics | Bombin H.,Copenhagen University
New Journal of Physics | Year: 2015

Color codes are topological stabilizer codes with unusual transversality properties. Here I show that their group of transversal gates is optimal and only depends on the spatial dimension, not the local geometry. I also introduce a generalized, subsystem version of color codes. In 3D they allow the transversal implementation of a universal set of gates by gauge fixing, while error-dectecting measurements involve only four or six qubits. © 2015 IOP Publishing Ltd and Deutsche Physikalische Gesellschaft.


Andersen M.H.,Copenhagen University
Immunologic Research | Year: 2014

The immune system is a complex arrangement of cells and molecules that preserve the integrity of the organism by eliminating all elements judged to be dangerous. Several regulatory mechanisms function to terminate immune responses to antigens, return the immune system to a basal state after the antigen has been cleared, and maintain unresponsiveness, or tolerance, to self-antigens. In recent years, reports have described T cell responses to several proteins involved in regulating the immune system, particularly under malignant conditions. The present review highlights specific T cells that recognize proteins involved in three, well-defined immunosuppressive mechanisms: (1) inhibitory T cell pathways (i.e., PD-L1), (2) regulatory T cells (i.e., Foxp3+), and (3) metabolic enzymes, like indoleamine-2,3-dioxygenase. Cytotoxic T cells can eliminate regulatory cells, thereby suppressing and/or delaying local immune suppression; conversely, regulatory CD4+ and non-cytotoxic CD8+ T cells enhance target-mediated immune suppression. The apparent lack of tolerance against endogenous proteins expressed by regulatory cells is intriguing, because it suggests that self-reactive T cells play a general role of fine-tuning the immune system. Thus, T cell responses may be generally used to maintain the homeostasis of the immune system. Further exploration is warranted to investigate the potential role of auto-reactive T cells under different physiological and/or pathological conditions. © 2014, Springer Science+Business Media New York.


Ostergaard M.,Copenhagen University
Seminars in Musculoskeletal Radiology | Year: 2012

This article reviews the utility of imaging in the diagnostic work-up of suspected and undifferentiated axial and peripheral inflammatory arthritis. Radiographic findings, that is, late damage but not early inflammation, are part of the classification criteria for rheumatoid arthritis (RA), ankylosing spondylitis, spondyloarthritis (SpA), and psoriatic arthritis (PsA), and they are generally part of the early examination program in arthritis. Computed tomography visualizes calcified tissue with high resolution but is rarely used unless radiography is unclear and MRI unavailable. MRI and ultrasonography (US) allow sensitive visualization and assessment of peripheral inflammatory and destructive joint and soft tissue involvement, and MRI is by far the best available method for detecting inflammation in the spine and sacroiliac joints in early SpA. Thus MRI/US can contribute to an earlier diagnosis of RA, PsA, and SpA. MRI and US are part of the recent American College of Rheumatology/ European League against Rheumatism 2010 classification criteria for RA (can be used to count involved joints), and MRI is part of the SpondyloArthritis International Society criteria for axial and peripheral SpA. Thus radiography, MRI, and/or US should be used in clinical practice to contribute to the diagnostic work-up in suspected, but not definite, inflammatory joint disease and early unclassified inflammatory joint disease, and they are also useful in establishing a specific diagnosis of RA. Radiography and particularly MRI are essential in establishing an early diagnosis of axial SpA. Copyright © 2012 by Thieme Medical Publishers, Inc.


Bonde J.P.,Copenhagen University
Asian Journal of Andrology | Year: 2010

Male reproductive disorders that are of interest from an environmental point of view include sexual dysfunction, infertility, cryptorchidism, hypospadias and testicular cancer. Several reports suggest declining sperm counts and increase of these reproductive disorders in some areas during some time periods past 50 years. Except for testicular cancer this evidence is circumstantial and needs cautious interpretation. However, the male germ line is one of the most sensitive tissues to the damaging effects of ionizing radiation, radiant heat and a number of known toxicants. So far occupational hazards are the best documented risk factors for impaired male reproductive function and include physical exposures (radiant heat, ionizing radiation, high frequency electromagnetic radiation), chemical exposures (some solvents as carbon disulfide and ethylene glycol ethers, some pesticides as dibromochloropropane, ethylendibromide and DDT/DDE, some heavy metals as inorganic lead and mercury) and work processes such as metal welding. Improved working conditions in affluent countries have dramatically decreased known hazardous workplace exposures, but millions of workers in less affluent countries are at risk from reproductive toxicants. New data show that environmental low-level exposure to biopersistent pollutants in the diet may pose a risk to people in all parts of the world. For other toxicants the evidence is only suggestive and further evaluation is needed before conclusions can be drawn. Whether compounds as phthalates, bisphenol A and boron that are present in a large number of industrial and consumer products entails a risk remains to be established. The same applies to psychosocial stressors and use of mobile phones. Finally, there are data indicating a particular vulnerability of the fetal testis to toxicantsfor instance maternal tobacco smoking. Time has come where male reproductive toxicity should be addressed form entirely new angles including exposures very early in life. © 2010 AJA, SIMM & SJTU All rights reserved.


Jacobsen S.-E.,Copenhagen University
Journal of Agronomy and Crop Science | Year: 2012

Winkel et al. (2012) have written a note called 'The sustainability of quinoa production in southern Bolivia: from misrepresentations to dubious solutions. A reply to S. Jacobsen', which is arguing against my paper (J. Agron. Crop Sci. 197, 2011, 390). In the following, I will respond to their main points. © 2012 Blackwell Verlag GmbH.


Our goal was to estimate the number of individuals with chronic obstructive pulmonary disease (COPD) in the Capital Region of Denmark and the need of resources required to implement the regional management programme for COPD. We examined a total of 45,970 participants from the Copenhagen General Population Study (CGPS) using spirometry and a questionnaire. The prevalence of spirometrically defined COPD among individuals older than 40 years of age was 15%, corresponding to 120,000 citizens in the Region. The number of individuals with moderate COPD (forced expiratory volume in one second (FEV1): 50-80% of predicted value) was estimated to approx. 51,000 (6.4%), whereas at least 10,000 (1.3%) were expected to have severe or very severe COPD (FEV1 < 50% of predicted value). Our estimates indicate that more than 26,000 individuals with moderate, severe or very severe COPD in the Region are smokers and that more than 19,000 qualify for physical training. We estimated that approx. 4,000 individuals with severe COPD were not treated with any inhaled medication. The Capital Region of Denmark needs to allocate substantial resources into early detection, rehabilitation and medical treatment of individuals with COPD in order to comply with the intentions of the Region's own management programme for COPD. The present analyses were sponsored by a grant from the Danish Ministry of Health. The CGPS was supported by the Copenhagen County Foundation, the Danish Medical Research Council and the Boserup Foundation. not relevant.


Lu J.-T.,Technical University of Denmark | Brandbyge M.,Technical University of Denmark | Hedegard P.,Copenhagen University
Nano Letters | Year: 2010

We examine a molecular bridge connecting two metallic electrodes. We find that an electronic current passing across the bridge can cause a vibrational instability of the molecule, which ultimately can lead to a breakdown of the bridge. This instability is generated by a hitherto never considered mechanism, which surprisingly involves the quantum mechanical phase of the electronic waves, the "Berry phase". This mechanism works for highly conducting bridges, and contrary to breakdown by traditional Joule heating, this instability is deterministic and occurs at certain critical voltages. We demonstrate the new mechanism using state-of-the-art ab initio calculations on realistic molecular bridges. © 2010 American Chemical Society.


Bombin H.,Perimeter Institute for Theoretical Physics | Bombin H.,Copenhagen University
Physical Review X | Year: 2015

Conventional quantum error correcting codes require multiple rounds of measurements to detect errors with enough confidence in fault-tolerant scenarios. Here, I show that for suitable topological codes, a single round of local measurements is enough. This feature is generic and is related to self-correction and confinement phenomena in the corresponding quantum Hamiltonian model. Three-dimensional gauge color codes exhibit this single-shot feature, which also applies to initialization and gauge fixing. Assuming the time for efficient classical computations to be negligible, this yields a topological fault-tolerant quantum computing scheme where all elementary logical operations can be performed in constant time.


Human and guinea pig fetuses are completely dependent on an adequate maternal vitamin C (vitC) intake. Shortage of micronutrients can have negative implications for fetal health and pregnancy outcome; however, knowledge of maternal vitC deficiency's impact on fetal development is sparse and reports of pregnancy outcome have been divergent. The present study investigated whether maternal vitC deficiency affects pregnancy outcome and plasma vitC distribution between the mother and the offspring in a guinea pig model. A total of eighty pregnant Dunkin Hartley guinea pigs were randomised into two weight-stratified groups receiving either a deficient (100 mg/kg DEF) or a control (923 mg/kg CTRL) diet. VitC levels were measured in plasma during pregnancy and postpartum, and in the plasma and brain of newborns. Pregnancy outcome was recorded with respect to birth weight and perinatal survival and were similar between groups. Plasma vitC in dams declined throughout gestation in both groups (P< 0·01). Compared with maternal plasma vitC, plasma vitC of newborn pups was found to be significantly lower in the DEF group (P< 0·001) and higher in the CTRL group (P< 0·001), respectively. Brain vitC levels were significantly reduced in DEF newborn pups (P< 0·001). The present results indicate that preferential transport of vitC from the mother to the fetus is overridden during sustained maternal vitC deficiency, maintaining maternal vitC concentration at the expense of the offspring. This contradicts the notion that a fetus is protected from vitC deficiency by the placental Na-dependent vitC co-transporter, SVCT2, thus fetal development may be susceptible to the negative effects of maternal vitC deficiency.


Despite its charismatic appeal to both scientists and the general public, remarkably little is known about the giant squid Architeuthis, one of the largest of the invertebrates. Although specimens of Architeuthis are becoming more readily available owing to the advancement of deep-sea fishing techniques, considerable controversy exists with regard to topics as varied as their taxonomy, biology and even behaviour. In this study, we have characterized the mitochondrial genome (mitogenome) diversity of 43 Architeuthis samples collected from across the range of the species, in order to use genetic information to provide new and otherwise difficult to obtain insights into the life of this animal. The results show no detectable phylogenetic structure at the mitochondrial level and, furthermore, that the level of nucleotide diversity is exceptionally low. These observations are consistent with the hypotheses that there is only one global species of giant squid, Architeuthis dux (Steenstrup, 1857), and that it is highly vagile, possibly dispersing through both a drifting paralarval stage and migration of larger individuals. Demographic history analyses of the genetic data suggest that there has been a recent population expansion or selective sweep, which may explain the low level of genetic diversity.


Skakkebaek N.E.,Copenhagen University
Asian Journal of Andrology | Year: 2010

Several recent studies have shown that the fecundity of a man decreases progressively with sperm concentrations below 40 million spermatozoa per mL. Therefore, it is unfortunate that the new World Health Organization guidelines for semen analysis recommend lowering the lower cutoff value for normal sperm concentration from 20 to 15 million spermatozoa per mL. As a result large groups of subfertile men across the world may not receive appropriate andrological help in the future. © 2010 AJA, SIMM & SJTU.


Hviid L.,Copenhagen University
Expert Review of Vaccines | Year: 2011

Vaccines are very cost-effective tools in combating infectious disease mortality and morbidity. Unfortunately, vaccines efficiently protecting against infection with malaria parasites are not available and are not likely to appear in the near future. An alternative strategy would be vaccines protecting against the disease and its consequences rather than against infection per se, by accelerating the development of the protective immunity that is normally acquired after years of exposure to malaria parasites in areas of stable transmission. This latter strategy is being energetically pursued to develop a vaccine protecting pregnant women and their offspring against mortality and morbidity caused by the accumulation of Plasmodium falciparum-infected erythrocytes in the placenta. It is based on a detailed understanding of the parasite antigen and the host receptor involved in this accumulation, as well as knowledge regarding the protective immune response that is acquired in response to placental P. falciparum infection. Nevertheless, it remains controversial in some quarters whether such a vaccine would have the desired impact, or indeed whether the strategy is meaningful. This article critically examines the relevance of several perceived obstacles to development of a vaccine against placental malaria. © 2011 Expert Reviews Ltd.


To understand the transformation pathways amongst anhydrate/hydrate solid forms of sodium naproxen and to highlight the importance of a polymorphic dihydrate within this context. Multi-temperature dynamic vapour sorption (DVS) analysis combined with variable-humidity X-ray powder diffraction (XRPD) to establish the transformation pathways as a function of temperature and humidity. XRPD and thermogravimetric analysis (TGA) to characterise bulk samples. Monitoring of in-situ dehydration using solid-state (13)C CP/MAS spectroscopy. At 25 °C, anhydrous sodium naproxen (AH) transforms directly to one dihydrate polymorph (DH-II). At 50 °C, AH transforms stepwise to a monohydrate (MH) then to the other dihydrate polymorph (DH-I). DH-II transforms to a tetrahydrate (TH) more readily than DH-I transforms to TH. Both dihydrate polymorphs transform to the same MH. The properties of the polymorphic dihydrate control the transformation pathways of sodium naproxen.


Thorsen R.S.,Copenhagen University
Health and Place | Year: 2015

Using the concept of 'therapeutic landscapes' this study explores how people in Nepal conceptualize their health care opportunities and how health care seeking practices are interpreted and experienced differently among people in their everyday contexts. Relational therapeutic landscapes were experienced through notions related to time and place as treatments were positioned along spectrums ranging from home to city and past to present. Conceptualizations of treatments were influenced by accessibility, lack of knowledge and uncertainties related to getting diagnosis as well as structural constraints beyond the health care system. © 2014 Elsevier Ltd.


Van De Weert M.,Copenhagen University
Journal of Fluorescence | Year: 2010

A number of recent articles, amongst others several published in the Journal of Fluorescence, use inappropriate fluorescence methodology to determine ligand binding characteristics to (mostly) proteins. In this Letter, several common pitfalls are discussed in relation to two recent publications in the Journal of Fluorescence (Wang et al. (2009) 19:801-808; Ding et al. (2009) 19:783-791). The Author hopes that this contribution helps to prevent a further spread of the incorrect methodology, and results in a reappraisal of those articles already published using similar methodology. © 2009 Springer Science+Business Media, LLC.


Honig S.F.,Copenhagen University
Astrophysical Journal Letters | Year: 2014

The time lag between optical and near-infrared (IR) flux variability can be taken as a means to determine the sublimation radius of the dusty "torus" around supermassive black holes in active galactic nuclei (AGNs). I will show that data from large optical survey telescopes, e.g., the Large Synoptic Survey Telescope (LSST), can be used to measure dust sublimation radii as well. The method makes use of the fact that the Wien tail of the hot dust emission reaches into the optical and can be reliably recovered with high-quality photometry. Simulations show that dust sublimation radii for a large sample of AGNs can be reliably established out to redshift z 0.1-0.2 with the LSST. Due to the ubiquitous presence of AGNs up to high redshifts, they have been studied as cosmological probes. Here, I discuss how optically determined dust time lags fit into the suggestion of using the dust sublimation radius as a "standard candle" and propose an extension of the dust time lags as "standard rulers" in combination with IR interferometry. © 2014. The American Astronomical Society. All rights reserved.


Padoan P.,University of Barcelona | Nordlund A.,Copenhagen University
Astrophysical Journal | Year: 2011

This work presents a new physical model of the star formation rate (SFR), which is verified with an unprecedented set of large numerical simulations of driven, supersonic, self-gravitating, magneto-hydrodynamic (MHD) turbulence, where collapsing cores are captured with accreting sink particles. The model depends on the relative importance of gravitational, turbulent, magnetic, and thermal energies, expressed through the virial parameter, αvir, the rms sonic Mach number, , and the ratio of mean gas pressure to mean magnetic pressure, β0. The SFR is predicted to decrease with increasing αvir (stronger turbulence relative to gravity), to increase with increasing (for constant values of αvir), and to depend weakly on β0 for values typical of star forming regions (-20 and β0 1-20). In the unrealistic limit of β0 → ∞, that is, in the complete absence of a magnetic field, the SFR increases approximately by a factor of three, which shows the importance of magnetic fields in the star formation process, even when they are relatively weak (super-Alfvénic turbulence). The star-formation simulations used to test the model result in an approximately constant SFR, after an initial transient phase. The dependence of the SFR on the virial parameter is shown to agree very well with the theoretical predictions. © 2011. The American Astronomical Society. All rights reserved..


Johansson P.I.,Copenhagen University
Current Opinion in Anaesthesiology | Year: 2012

Purpose of review: Death due to trauma is the leading cause of lost life years worldwide, with haemorrhage being responsible for 30-40% of trauma mortality and accounting for almost 50% of the deaths in the initial 24 h. On admission, 25-35% of trauma patients present with coagulopathy, which is associated with a several-fold increase in morbidity and mortality. Recent findings: Plasma-based routine coagulation tests, like prothrombin time and activated partial thromboplastin time, are inappropriate for monitoring coagulopathy and guide therapy in trauma patients. Instead viscoelastic haemostatic assays (VHAs) such as thrombelastography and rotation thromboelastometry should be used. Clinical studies including about 1500 trauma patients have reported on the benefit of using the VHAs to identify coagulopathy, predict need for massive transfusion and enable goal-directed therapy. Summary: This article reviews the basic principles of VHA, the correlation between the VHA whole blood clot formation in accordance with the cell-based model of haemostasis, the current use of VHA-guided therapy in trauma and limitations of VHA. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Olesen J.,Copenhagen University
Neurotherapeutics | Year: 2010

Summary: Nitric oxide (NO) is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also involved in nociceptive processing. Glyceryl trinitrate (GTN), a pro-drug for NO, causes headache in normal volunteers and a so-called delayed headache that fulfils criteria for migraine without aura in migraine sufferers. Blockade of nitric oxide synthases (NOS) by L-nitromonomethylarginine effectively treats attacks of migraine without aura. Similar results have been obtained for chronic the tension-type headache and cluster headache. Inhibition of the breakdown of cyclic guanylate phosphate (cGMP) also provokes migraine in sufferers, indicating that cGMP is the effector of NO-induced migraine. Similar evidence suggests an important role of NO in the tension-type headache and cluster headache. These very strong data from human experimentation make it highly likely that antagonizing NO effects will be effective in the treatment of primary headaches. Nonselective NOS inhibitors are likely to have side effects whereas selective compounds are now in early clinical trials. Antagonizing the rate limiting cofactor tetrahydrobiopterin seems another very likely new treatment. It is more unlikely that antagonism of cGMP or its formation will be feasible, but augmenting its breakdown via phosphodiesterase activation is a possibility, as well as other ways of inhibiting the NO-cGMP pathway. © 2010 The American Society for Experimental NeuroTherapeutics, Inc.


Blok A.,Copenhagen University
Science Technology and Human Values | Year: 2011

This article examines some of the difficulties of universalistic science in situations of deep conflict over global nature, using empirical material pertaining to ongoing controversies in the context of Japanese whaling practices. Within global-scale whaling assemblages since the 1970s, science has become a "post-sovereigna" authority, unable to impose any stable definition of nature on all actors. Instead, across spaces of deep antagonistic differences, anti- and pro-whalers now ontologically enact a multiplicity of mutually irreconcilable versions of whales. Empirically, the article attempts to map out a "cosmograma" of Japanese pro-whaling enactments of abundant and "killablea" whales. Following the political ecology of Bruno Latour, the global-scale situation is conceptualized as one of cosmopolitics, the politics of forging a common world across divergences in nature-cultures. Pointing to tensions inherent in this concept, the article ends by suggesting a move toward "agonistic cosmopolitics," in clarifying the constructive potentials of a Latourian anti-essentialist political ecology. © The Author(s) 2011.


Michaelsen K.F.,Copenhagen University | Greer F.R.,University of Wisconsin - Madison
American Journal of Clinical Nutrition | Year: 2014

The objective of this review was to summarize selected health aspects of protein intake during the first 2 y of life. During this period there is a marked increase in protein intake from an intake of ∼5% of energy from protein (PE%) in an exclusively breastfed infant to ∼15 PE% when complementary foods have been introduced. At this age, mean protein intake is ∼3 times as high as the physiologic requirement, but some children receive 4-5 times their physiologic requirement. Protein from cow milk constitutes a main part of protein intake in toddlers and seems to have a specific effect on insulin-like growth factor I concentrations and growth. Meat has a high protein content, but the small amounts of meat needed to ensure good iron status have less impact on total protein intake. The difference in protein intake between breastfed and formula-fed infants is likely to play a role in the difference between breastfed and formula-fed infants. There is emerging evidence that high protein intake during the first 2 y of life is a risk factor for later development of overweight and obesity. It therefore seems prudent to avoid a high protein intake during the first 2 y of life. This could be accomplished by decreasing the upper allowable limit of the protein content of infant formulas for the first year of life and limiting the intake of cow milk in the second year of life. © 2014 American Society for Nutrition.


Rasmussen T.,Copenhagen University
European heart journal cardiovascular Imaging | Year: 2013

Cardiovascular conditions are reported to be the most frequent cause of death in patients with chronic obstructive pulmonary disease (COPD). However, it remains unsettled whether severity of COPD per se is associated with coronary artery disease (CAD) independent of traditional cardiovascular risk factors. The aim of this study was to examine the relationship between the presence and severity of COPD and the amount of coronary artery calcium deposit, an indicator of CAD and cardiac risk, in a large population of current and former long-term smokers. In this cross-sectional study, long-term smokers without clinically manifested CAD were recruited from the Danish Lung Cancer Screening Trial and classified according to lung function by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Coronary artery calcium deposit as a measure of subclinical CAD and cardiac risk was evaluated with multi detector computed tomography and the Agatston coronary artery calcium score (CACS). Participants were categorized into five CACS risk classification groups according to the CACS. The population (n = 1535) consisted of 41% participants without COPD, 28% with mild, and 31% with moderate-to-severe COPD (n = 46 with severe COPD). In addition to age, male gender, hypertension, hypercholesterolaemia, and continued smoking, COPD according to GOLD classification were independent predictors of a higher CACS risk classification group in multivariable analysis [odds ratio (OR): 1.28 (1.01-1.63) and OR: 1.32 (1.05-1.67), for mild and moderate-to-severe COPD, respectively, compared with no COPD]. COPD in long-term smokers is independently correlated with the CACS, while COPD severity per se does not show a dose-response relationship.


Rosenberg J.,Copenhagen University
Journal of Alzheimer's Disease | Year: 2016

Zeng et al.'s Ethics Review highlights some of the challenges associated with clinical research in China. They found that only a minority of published clinical trials of anti-dementia drugs reported that they fulfilled the basic ethical principles as outlined in the Declaration of Helsinki. With recent reports of scientific misconduct from China, there is an urgent need to find approaches to compel researchers to adhere to ethical research practices. This problem does not call for a simple solution, but if forces are joined with governmental regulations, education in ethics issues for medical researchers, and strong reinforcement by Chinese journal editors not to publish studies with these flaws, then research ethics and publication standards will probably improve. Other solutions to foster ethical practice of drug trials are discussed including Chinese initiatives directed at managing conflict of interest from the pharmaceutical industry and educating clinical researchers. © 2016 - IOS Press and the authors. All rights reserved.


Bjarnsholt T.,Copenhagen University
APMIS. Supplementum | Year: 2013

Acute infections caused by pathogenic bacteria have been studied extensively for well over 100 years. These infections killed millions of people in previous centuries, but they have been combated effectively by the development of modern vaccines, antibiotics and infection control measures. Most research into bacterial pathogenesis has focused on acute infections, but these diseases have now been supplemented by a new category of chronic infections caused by bacteria growing in slime-enclosed aggregates known as biofilms. Biofilm infections, such as pneumonia in cystic fibrosis patients, chronic wounds, chronic otitis media and implant- and catheter-associated infections, affect millions of people in the developed world each year and many deaths occur as a consequence. In general, bacteria have two life forms during growth and proliferation. In one form, the bacteria exist as single, independent cells (planktonic) whereas in the other form, bacteria are organized into sessile aggregates. The latter form is commonly referred to as the biofilm growth phenotype. Acute infections are assumed to involve planktonic bacteria, which are generally treatable with antibiotics, although successful treatment depends on accurate and fast diagnosis. However, in cases where the bacteria succeed in forming a biofilm within the human host, the infection often turns out to be untreatable and will develop into a chronic state. The important hallmarks of chronic biofilm-based infections are extreme resistance to antibiotics and many other conventional antimicrobial agents, and an extreme capacity for evading the host defences. In this thesis, I will assemble the current knowledge on biofilms with an emphasis on chronic infections, guidelines for diagnosis and treatment of these infections, before relating this to my previous research into the area of biofilms. I will present evidence to support a view that the biofilm lifestyle dominates chronic bacterial infections, where bacterial aggregation is the default mode, and that subsequent biofilm development progresses by adaptation to nutritional and environmental conditions. I will make a series of correlations to highlight the most important aspects of biofilms from my perspective, and to determine what can be deduced from the past decades of biofilm research. I will try to bridge in vitro and in vivo research and propose methods for studying biofilms based on this knowledge. I will compare how bacterial biofilms exist in stable ecological habitats and opportunistically in unstable ecological habitats, such as infections. Bacteria have a similar lifestyle (the biofilm) in both habitats, but the fight for survival and supremacy is different. On the basis of this comparison, I will hypothesize how chronic biofilm infections are initiated and how bacteria live together in these infections. Finally, I will discuss different aspects of biofilm infection diagnosis. Hopefully, this survey of current knowledge and my proposed guidelines will provide the basis and inspiration for more research, improved diagnostics, and treatments for well-known biofilm infections and any that may be identified in the future. © 2013 APMIS Published by Blackwell Publishing Ltd.


Maisonneuve E.,Northumbria University | Gerdes K.,Northumbria University | Gerdes K.,Copenhagen University
Cell | Year: 2014

All bacteria form persisters, cells that are multidrug tolerant and therefore able to survive antibiotic treatment. Due to the low frequencies of persisters in growing bacterial cultures and the complex underlying molecular mechanisms, the phenomenon has been challenging to study. However, recent technological advances in microfluidics and reporter genes have improved this scenario. Here, we summarize recent progress in the field, revealing the ubiquitous bacterial stress alarmone ppGpp as an emerging central regulator of multidrug tolerance and persistence, both in stochastically and environmentally induced persistence. In several different organisms, toxin-antitoxin modules function as effectors of ppGpp-induced persistence. © 2014 Elsevier Inc.


The serotonin transporter (SERT) controls synaptic serotonin levels and is the primary target for antidepressants, including selective serotonin reuptake inhibitors (e.g. (S)-citalopram) and tricyclic antidepressants (e.g. clomipramine). In addition to a high affinity binding site, SERT possesses a low affinity allosteric site for antidepressants. Binding to the allosteric site impedes dissociation of antidepressants from the high affinity site, which may enhance antidepressant efficacy. Here we employ an induced fit docking/molecular dynamics protocol to identify the residues that may be involved in the allosteric binding in the extracellular vestibule located above the central substrate binding (S1) site. Indeed, mutagenesis of selected residues in the vestibule reduces the allosteric potency of (S)-citalopram and clomipramine. The identified site is further supported by the inhibitory effects of Zn(2+) binding in an engineered site and the covalent attachment of benzocaine-methanethiosulfonate to a cysteine introduced in the extracellular vestibule. The data provide a mechanistic explanation for the allosteric action of antidepressants at SERT and suggest that the role of the vestibule is evolutionarily conserved among neurotransmitter:sodium symporter proteins as a binding pocket for small molecule ligands.


Langstrup H.,Copenhagen University
Science Technology and Human Values | Year: 2011

The author traces the ways in which various patients and collective associations of patients come to regard themselves as the users of future stem cell technologies. The author uses Althusser's notion of interpellation (1971/2006), whereby an identity is the result of the situated encounter of a subject and an authority, to analyze the ways in which patient associations' current involvement with basic research is related to the enactment of science as a series of technology development projects. The author argues that this "project-ness" forms a certain privileged logic that interpellates patients and their associations in specific ways. Through the listings of illnesses circulated in the mass media, which are hoped to be treatable or curable with stem cell therapies, patients come to recognize themselves as the projected users of stem cell technologies. The author fleshes out the process of this userfication and the various responses made by patients and their associations when hailed by the entrepreneurial projects of stem cell research. © The Author(s) 2011.


Silicon nanowire (Si NW)-based field effect transistors (FETs) have shown great potential as biosensors (bioFETs) for ultra-sensitive and label-free detection of biomolecular interactions. Their sensitivity depends not only on the device properties, but also on the function of the biological recognition motif attached to the Si NWs. In this study, we show that SiNWs can be chemically functionalized with Ni:NTA motifs, suitable for the specific immobilization of proteins via a short polyhistidine tag (His-tag) at close proximity to the SiNW surface. We demonstrate that the proteins preserve their function upon immobilization onto SiNWs. Importantly, the protein immobilization on the Si NWs is shown to be reversible after addition of EDTA or imidazole, thus allowing the regeneration of the bioFET when needed, such as in the case of proteins having a limited lifetime. We anticipate that our methodology may find a generic use for the development of bioFETs exploiting functional protein assays because of its high compatibility to various types of NWs and proteins.


Thyssen J.P.,Copenhagen University
Dermatitis | Year: 2012

This clinical review article presents clinical and scientific data on cobalt sensitization and dermatitis. It is concluded that cobalt despite being a strong sensitizer and a prevalent contact allergen to come up on patch testing should be regarded as a very complex metal to test with. Exposure data together with clinical data from metal workers heavily exposed to cobalt suggest that patch-test reactions are sometimes false positive and that patch testers should carefully evaluate their clinical relevance. © 2012 American Contact Dermatitis Society. All Rights Reserved.


Faye J.,Copenhagen University
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2016

The Copenhagen interpretation is first and foremost associated with Niels Bohr's philosophy of quantum mechanics. In this paper, I attempt to lay out what I see as Bohr's pragmatic approach to science in general and to quantum physics in particular. A part of this approach is his claim that the classical concepts are indispensable for our understanding of all physical phenomena, and it seems as if the claim is grounded in his reflection upon how the evolution of language is adapted to experience. Another, recent interpretation, QBism, has also found support in Darwin's theory. It may therefore not be surprising that sometimes QBism is said to be of the same breed as the Copenhagen interpretation. By comparing the two interpretations, I conclude, nevertheless, that there are important differences. © 2016 The Author(s) Published by the Royal Society.


Berg P.,Karlsruhe Institute of Technology | Berg P.,Swedish Meteorological and Hydrological Institute | Moseley C.,Max Planck Institute for Meteorology | Moseley C.,Helmholtz Center Geesthacht | Haerter J.O.,Copenhagen University
Nature Geoscience | Year: 2013

Precipitation changes can affect society more directly than variations in most other meteorological observables1-3, but precipitation is difficult to characterize because of fluctuations on nearly all temporal and spatial scales. In addition, the intensity of extreme precipitation rises markedly at higher temperature4-9, faster than the rate of increase in the atmosphere's water-holding capacity1,4, termed the Clausius-Clapeyron rate. Invigoration of convective precipitation (such as thunderstorms) has been favoured over a rise in stratiform precipitation (such as large-scale frontal precipitation) as a cause for this increase 4,10, but the relative contributions of these two types of precipitation have been difficult to disentangle. Here we combine large data sets from radar measurements and rain gauges over Germany with corresponding synoptic observations and temperature records, and separate convective and stratiform precipitation events by cloud observations. We find that for stratiform precipitation, extremes increase with temperature at approximately the Clausius-Clapeyron rate, without characteristic scales. In contrast, convective precipitation exhibits characteristic spatial and temporal scales, and its intensity in response to warming exceeds the Clausius-Clapeyron rate. We conclude that convective precipitation responds much more sensitively to temperature increases than stratiform precipitation, and increasingly dominates events of extreme precipitation. Copyright © 2013 Macmillan Publishers Limited.


Munch-Andersen T.,Copenhagen University
International journal of circumpolar health | Year: 2012

To evaluate the effect of regular physical activity on metabolic risk factors and blood pressure in Inuit with high BMI consuming a western diet (high amount of saturated fatty acids and carbohydrates with a high glycemic index). Cross sectional study, comparing Inuit eating a western diet with Inuit eating a traditional diet. Two physically active Greenland Inuit groups consuming different diet, 20 eating a traditional diet (Qaanaaq) and 15 eating a western diet (TAB), age (mean (range)); 38, (22-58) yrs, BMI; 28 (20-40) were subjected to an oral glucose tolerance test (OGTT), blood sampling, maximal oxygen uptake test, food interview/collection and monitoring of physical activity. All Inuit had a normal OGTT. Fasting glucose (mmol/l), HbA1c (%), total cholesterol (mmol/l) and HDL-C (mmol/l) were for Qaanaaq women: 4.8±0.2, 5.3±0.1, 4.96±0.42, 1.34±0.06, for Qaanaaq men: 4.9±0.1, 5.7±0.1, 5.08±0.31, 1.28±0.09, for TAB women: 5.1±0.2, 5.3±0.1, 6.22±0.39, 1.86±0.13, for TAB men: 5.1±0.2, 5.3±0.1, 6.23±0.15, 1.60±0.10. No differences were found in systolic or diastolic blood pressure between the groups. There was a more adverse distribution of small dense LDL-C particles and higher total cholesterol and HDL-C concentration in the western diet group. Diabetes or impaired glucose tolerance was not found in the Inuit consuming either the western or the traditional diet, and this could, at least partly, be due to the high amount of regular daily physical activity. However, when considering the total cardio vascular risk profile the Inuit consuming a western diet had a less healthy profile than the Inuit consuming a traditional diet.


Immunogenicity of biopharmaceuticals is complex and influenced by both structural and pharmacological factors, and by patient-related conditions such as disease being treated, previous and concomitant therapies, and individual immune responsiveness. Essential for tailored therapeutic strategies based on immunopharmacological evidence from individual patients (personalized medicine) is the use of assays for anti-drug antibodies (ADA) that are accurate and relevant in the clinical setting. This paper discusses immunogenicity of genetically engineered immunoglobulins directed against tumor-necrosis factor-α (TNF). Emphasis will be on commonly used methods for detection of ADA in human serum including issues that question the clinical applicability of these methodologies. The use of dubious assays for ADA in a clinical context may not only contribute to confusion as to the importance of drug immunogenicity but may also prevent development of safe and cost-effective ways of using biological TNF-antagonists. © 2015 Bendtzen.


To assess the risk of venous thromboembolism from use of combined oral contraceptives according to progestogen type and oestrogen dose. National historical registry based cohort study. Four registries in Denmark. Non-pregnant Danish women aged 15-49 with no history of thrombotic disease and followed from January 2001 to December 2009. Relative and absolute risks of first time venous thromboembolism. Within 8,010,290 women years of observation, 4307 first ever venous thromboembolic events were recorded and 4246 included, among which 2847 (67%) events were confirmed as certain. Compared with non-users of hormonal contraception, the relative risk of confirmed venous thromboembolism in users of oral contraceptives containing 30-40 μg ethinylestradiol with levonorgestrel was 2.9 (95% confidence interval 2.2 to 3.8), with desogestrel was 6.6 (5.6 to 7.8), with gestodene was 6.2 (5.6 to 7.0), and with drospirenone was 6.4 (5.4 to 7.5). With users of oral contraceptives with levonorgestrel as reference and after adjusting for length of use, the rate ratio of confirmed venous thromboembolism for users of oral contraceptives with desogestrel was 2.2 (1.7 to 3.0), with gestodene was 2.1 (1.6 to 2.8), and with drospirenone was 2.1 (1.6 to 2.8). The risk of confirmed venous thromboembolism was not increased with use of progestogen only pills or hormone releasing intrauterine devices. If oral contraceptives with desogestrel, gestodene, or drospirenone are anticipated to increase the risk of venous thromboembolism sixfold and those with levonorgestrel threefold, and the absolute risk of venous thromboembolism in current users of the former group is on average 10 per 10,000 women years, then 2000 women would need to shift from using oral contraceptives with desogestrel, gestodene, or drospirenone to those with levonorgestrel to prevent one event of venous thromboembolism in one year. After adjustment for length of use, users of oral contraceptives with desogestrel, gestodene, or drospirenone were at least at twice the risk of venous thromboembolism compared with users of oral contraceptives with levonorgestrel.


Hasselbalch H.C.,Copenhagen University
Cytokine and Growth Factor Reviews | Year: 2013

Myelofibrosis (MF) is a life-threatening blood cancer characterized by progressive bone marrow fibrosis, splenomegaly, cytopenias, and debilitating constitutional symptoms. Abnormal expression and activity of a number of proinflammatory cytokines are associated with MF, in which immune dysregulation is pronounced as evidenced by dysregulation of several immune and inflammation genes. The discovery of the Janus kinase 2 (JAK2) V617F mutation has led to the development of a number of JAK1/2 inhibitors in the treatment of MF and similar neoplasms. Here, the role of cytokines in MF initiation and progression is discussed, the impact of current therapies is reviewed, and new combination therapies are proposed, such as JAK1/2 inhibitors with interferons, statins, and epigenetic modifiers for patients with MF and related neoplasms. © 2013 Elsevier Ltd.


Introduction of reperfusion therapy by primary percutaneous coronary intervention (PCI) has resulted in improved outcomes for patients presenting with ST-segment elevation myocardial infarction. Despite the obvious advantages of primary PCI, acute restoration of blood flow paradoxically also jeopardises the myocardium in the first minutes of reperfusion - a phenomenon known as reperfusion injury. Prevention of reperfusion injury may help to improve outcome following primary PCI. This review focuses on the clinical evidence of potential therapeutic cardioprotective methods as adjuvant to primary PCI. Despite overall disappointing, there exists some promising strategies, including ischaemic postconditioning, remote ischaemic conditioning, pharmacological conditioning with focus on adenosine, cyclosporine A, glucose-insulin-potassium, exenatide, atrial natriuretic peptide and metoprolol and cooling. But hitherto no large randomised study has demonstrated any effect on outcome, and ongoing studies that address this issue are underway. Moreover, this review will discuss important clinical predictors associated with reperfusion injury during primary PCI that may interfere with a potential protective effect (pre-PCI thrombolysis in myocardial infarction flow, preinfarction angina, collateral flow, duration of ischaemia and hyperglycaemia). This paper will also provide a short overview of the technical issues related to surrogate endpoints in phase II trials. Based upon these discussions, the paper will provide factors that should be taken into account when designing future clinical studies.


Andersen M.H.,Copenhagen University
Cancer Immunology, Immunotherapy | Year: 2012

Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in many settings including cancer. In recent years, we have described spontaneous CD8+ as well as CD4+ T-cell reactivity against IDO in the tumor microenvironment of different cancer patients as well as in the peripheral blood of both cancer patients and to a lesser extent in healthy donors. We have demonstrated that IDOreactive CD8+ T cells were peptide-specific, cytotoxic effector cells, which are able to recognize and kill IDOexpressing cells including tumor cells as well as dendritic cells. Consequently, IDO may serve as a widely applicable target for immunotherapeutic strategies with a completely different function as well as expression pattern compared to previously described antigens. IDO constitutes a significant counter-regulatory mechanism induced by proinflammatory signals, and IDO-based immunotherapy may consequently be synergistic with additional immunotherapy. In this regard, we have shown that the presence of IDO-specific T cells boosted immunity against CMV and tumor antigens by eliminating IDO? suppressive cells and changing the regulatory microenvironment. The current review summarizes current knowledge of IDO as a T-cell antigen, reports the initial results that are suggesting a general function of IDO-specific T cells in immunoregulation, and discusses future opportunities. © Springer-Verlag 2012.


Jones C.,Molecular Therapeutics | Perryman L.,Copenhagen University | Hargrave D.,Great Ormond Street Hospital
Nature Reviews Clinical Oncology | Year: 2012

Gliomas in children differ from their adult counterparts by their distribution of histological grade, site of presentation and rate of malignant transformation. Although rare in the paediatric population, patients with high-grade gliomas have, for the most part, a comparably dismal clinical outcome to older patients with morphologically similar lesions. Molecular profiling data have begun to reveal the major genetic alterations underpinning these malignant tumours in children. Indeed, the accumulation of large datasets on adult high-grade glioma has revealed key biological differences between the adult and paediatric disease. Furthermore, subclassifications within the childhood age group can be made depending on age at diagnosis and tumour site. However, challenges remain on how to reconcile clinical data from adult patients to tailor novel treatment strategies specifically for paediatric patients. © 2012 Macmillan Publishers Limited. All rights reserved.


The morbidity and mortality of patients with the chronic Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera, and primary myelofibrosis are mainly caused by cardiovascular diseases, thrombohemorrhagic complications, and bone marrow failure because of myelofibrosis and leukemic transformation. In the general population, chronic inflammation is considered of major importance for the development of atherosclerosis and cancer. MPNs are characterized by a state of chronic inflammation, which is proposed to be the common denominator for the development of "premature atherosclerosis," clonal evolution, and second cancer in patients with MPNs. Chronic inflammation may both initiate clonal evolution and catalyze its expansion from early disease stage to the myelofibrotic burnt-out phase. Furthermore, chronic inflammation may also add to the severity of cardiovascular disease burden by accelerating the development of atherosclerosis, which is well described and recognized in other chronic inflammatory diseases. A link between chronic inflammation, atherosclerosis, and second cancer in MPNs favors early intervention at the time of diagnosis (statins and interferon-α2), the aims being to dampen chronic inflammation and clonal evolution and thereby also diminish concurrent disease-mediated chronic inflammation and its consequences (accelerated atherosclerosis and second cancer). © 2012 by The American Society of Hematology.


Kierkegaard P.,Copenhagen University
Computer Law and Security Review | Year: 2011

The European Commission wants to boost the digital economy by enabling all Europeans to have access to online medical records anywhere in Europe by 2020. With the newly enacted Directive 2011/24/EU on patients' rights in cross-border healthcare due for implementation by 2013, it is inevitable that a centralised European health record system will become a reality even before 2020. However, the concept of a centralised supranational central server raises concern about storing electronic medical records in a central location. The privacy threat posed by a supranational network is a key concern. Cross-border and Interoperable electronic health record systems make confidential data more easily and rapidly accessible to a wider audience and increase the risk that personal data concerning health could be accidentally exposed or easily distributed to unauthorised parties by enabling greater access to a compilation of the personal data concerning health, from different sources, and throughout a lifetime. © 2011 Baker & McKenzie LLP. Published by Elsevier Ltd. All rights reserved.


Albrechtsen A.,Copenhagen University | Nielsen F.C.,Rigshospitalet | Nielsen R.,University of California at Berkeley
Molecular Biology and Evolution | Year: 2010

Chip-based high-throughput genotyping has facilitated genome-wide studies of genetic diversity. Many studies have utilized these large data sets to make inferences about the demographic history of human populations using measures of genetic differentiation such as FST or principal component analyses. However, the single nucleotide polymorphism (SNP) chip data suffer from ascertainment biases caused by the SNP discovery process in which a small number of individuals from selected populations are used as discovery panels. In this study, we investigate the effect of the ascertainment bias on inferences regarding genetic differentiation among populations in one of the common genome-wide genotyping platforms. We generate SNP genotyping data for individuals that previously have been subject to partial genome-wide Sanger sequencing and compare inferences based on genotyping data to inferences based on direct sequencing. In addition, we also analyze publicly available genome-wide data. We demonstrate that the ascertainment biases will distort measures of human diversity and possibly change conclusions drawn from these measures in some times unexpected ways. We also show that details of the genotyping calling algorithms can have a surprisingly large effect on population genetic inferences. We not only present a correction of the spectrum for the widely used Affymetrix SNP chips but also show that such corrections are difficult to generalize among studies. © 2010 The Author.


Bendtzen K.,Copenhagen University
Immunotherapy | Year: 2012

This article discusses the rationale behind recommending immunopharmacological guidance of long-term therapies with genetically engineered anti-TNF-α immunoglobulin constructs. Arguments why therapeutic decision-making should not rely on clinical outcome alone are presented. Central to this is that the use of theranostics (i.e., monitoring circulating levels of functional anti-TNF-α drugs and antidrug antibodies) would markedly improve treatment because therapies can be tailored to individual patients and provide more effective and economical long-term therapies with minimal risk of side effects. Large-scale immunopharmacological knowledge of how patients 'handle TNF-α biopharmaceuticals would also help industry develop more effective and safer TNF-α inhibitors. © 2012 Future Medicine Ltd.


Fynbo L.,Copenhagen University
British Journal of Criminology | Year: 2011

The paper analyses risk behaviour as described by a group of convicted drink-drivers. Risk assessment is seen as a part of a complicated process reflecting moral values in specific socio-cultural settings and within a specific framework of time. The respondents' retrospective accounts of their drink-driving are interpreted as part of moral identity negotiations, focusing on four dimensions: drink-driving as non-voluntary behaviour, drink-driving as strategic behaviour, drink-driving and control, and drink-driving and 'normalcy'. Central to these negotiations is the fact that many respondents come from social environments (be that friend groups or workmate groups) where drink-driving is common and that they therefore do not regard - or did not regard - drink-driving as deviant behaviour. © The Author 2011. Published by Oxford University Press on behalf of the Centre for Crime and Justice Studies (ISTD). All rights reserved.


Christensen A.E.,Copenhagen University
Natural Resources Forum | Year: 2011

The rise and fall of the bêche-de-mer trade in Solomon Islands is an example of how small, remote island communities are influenced by drivers of change on both the national and international scales. This susceptibility leads to local economic collapses and changed livelihoods. This article focuses on small-island livelihoods, socio-economic responses to fluctuating markets and the instability caused by internal and external forces of change. Quantitative surveys, qualitative interviews and participant observation have been used to explore the development trajectories of Ontong Java, a Polynesian outlier in Solomon Islands, in the context of the bêche-de-mer trade over the past forty years. The main findings can be captured in four distinct periods that demonstrate the transformation of this atoll community from subsistence-oriented strategies to specialization in marine resource extraction to economic collapse and return to subsistence. It is concluded that this atoll population has shown a remarkable ability to adjust and cope with processes of globalization. © 2011 The Author. Natural Resources Forum © 2011 United Nations.


Cocktail effects and synergistic interactions of chemicals in mixtures are an area of great concern to both the public and regulatory authorities. The main concern is whether some chemicals can enhance the effect of other chemicals, so that they jointly exert a larger effect than predicted. This phenomenon is called synergy. Here we present a review of the scientific literature on three main groups of environmentally relevant chemical toxicants: pesticides, metal ions and antifouling compounds. The aim of the review is to determine 1) the frequency of synergy, 2) the extent of synergy, 3) whether any particular groups or classes of chemicals tend to induce synergy, and 4) which physiological mechanisms might be responsible for this synergy. Synergy is here defined as mixtures with minimum two-fold difference between observed and predicted effect concentrations using Concentration Addition (CA) as a reference model and including both lethal and sublethal endpoints. The results showed that synergy occurred in 7%, 3% and 26% of the 194, 21 and 136 binary pesticide, metal and antifoulants mixtures included in the data compilation on frequency. The difference between observed and predicted effect concentrations was rarely more than 10-fold. For pesticides, synergistic mixtures included cholinesterase inhibitors or azole fungicides in 95% of 69 described cases. Both groups of pesticides are known to interfere with metabolic degradation of other xenobiotics. For the four synergistic metal and 47 synergistic antifoulant mixtures the pattern in terms of chemical groups inducing synergy was less clear. Hypotheses in terms of mechanisms governing these interactions are discussed. It was concluded that true synergistic interactions between chemicals are rare and often occur at high concentrations. Addressing the cumulative rather than synergistic effect of co-occurring chemicals, using standard models as CA, is therefore regarded as the most important step in the risk assessment of chemical cocktails. © 2014 Nina Cedergreen.


Kliebenstein D.J.,University of California at Davis | Kliebenstein D.J.,Copenhagen University
Current Opinion in Plant Biology | Year: 2014

A goal of metabolic engineering is to take a plant and introduce new or modify existing pathways in a directed and predictable fashion. However, existing data does not provide the necessary level of information to allow for predictive models to be generated. One avenue to reverse engineer the necessary information is to study the genetic control of natural variation in plant primary and secondary metabolism. These studies are showing that any engineering model will have to incorporate information about 1000s of genes in both the nuclear and organellar genome to optimize the function of the introduced pathway. Further, these genes may interact in an unpredictable fashion complicating any engineering approach as it moves from the one or two gene manipulation to higher order stacking efforts. Finally, metabolic engineering may be influenced by a previously unrecognized potential for a plant to measure the metabolites within it. In combination, these observations from natural variation provide a beginning to help improve current efforts at metabolic engineering. © 2014 Elsevier Ltd.


Grantcharov T.P.,University of Toronto | Kehlet H.,Copenhagen University
British Journal of Surgery | Year: 2010

Background: Laparoscopy is associated with less pain and organ dysfunction than open surgery. Improved perioperative care (enhanced recovery programmes, fast-track methodology) has also led to reduced morbidity and a shorter hospital stay. The effects of a combination of laparoscopic resection and accelerated recovery have not been examined previously in the context of gastric surgery. Methods: This was a prospective study of 32 consecutive patients undergoing laparoscopic gastric resection combined with an enhanced recovery protocol (early oral intake, no drains or nasogastric tubes, no epidural analgesia, use of a urinary catheter for less than 24 h and planned discharge 72 h after surgery). Outcomes included length of hospital stay, intraoperative and postoperative complications, readmission rate and 30-day mortality. Results: Operative procedures were elective distal or subtotal gastrectomy (22 patients) and total gastrectomy (10). Median length of hospital stay was 4 (range 2-30) days. There were two major complications: postoperative bleeding requiring reoperation and pulmonary embolism. Two patients required readmission, one for a wound abscess and one for treatment of a urinary tract infection. There were no deaths within 30 days. Conclusion: Minimally invasive gastrectomy with enhanced postoperative recovery results in a short hospital stay and low morbidity rate. © 2010 British Journal of Surgery Society Ltd.


Herranen M.,Copenhagen University | Markkanen T.,Helsinki Institute of Physics | Nurmi S.,Helsinki Institute of Physics | Rajantie A.,Imperial College London
Physical Review Letters | Year: 2014

It has been claimed that the electroweak vacuum may be unstable during inflation due to large fluctuations of the order H in the case of a high inflationary scale as suggested by BICEP2. We compute the standard model Higgs effective potential including UV-induced curvature corrections at one-loop level. We find that for a high inflationary scale a large curvature mass is generated due to renormalization group running of nonminimal coupling ξ, which either stabilizes the potential against fluctuations for ξEW6×10-2, or destabilizes it for ξEW2×10-2 when the generated curvature mass is negative. Only in the narrow intermediate region may the effect of the curvature mass be significantly smaller. © 2014 American Physical Society.


Tomba E.,University of Bologna | Bech P.,Copenhagen University
Psychotherapy and Psychosomatics | Year: 2012

Background: Clinimetrics was introduced three decades ago to specify the domain of clinical markers in clinical medicine (indexes or rating scales). In this perspective, clinical validity is the platform for selecting the various indexes or rating scales (macro-analysis). Psychometric validation of these indexes or rating scales is the measuring aspect (micro-analysis). Methods: Clinical judgment analysis by experienced psychiatrists is included in the macro-analysis and the item response theory models are especially preferred in the micro-analysis when using the total score as a sufficient statistic. Results: Clinical assessment tools covering severity of illness scales, prognostic measures, issues of co-morbidity, longitudinal assessments, recovery, stressors, lifestyle, psychological well-being, and illness behavior have been identified. Conclusion: The constructive dialogue in clinimetrics between clinical judgment and psychometric validation procedures is outlined for generating developments of clinical practice in psychiatry. Copyright © 2012 S. Karger AG, Basel.


In this thesis the term eye amputation (EA) covers the removing of an eye by: evisceration, enucleation and exenteration. Amputation of an eye is most frequently the end-stage in a complicated disease, or the primary treatment in trauma and neoplasm. In 2010 the literature is extensive due to knowledge about types of surgery, implants and surgical technique. However, not much is known about the time past surgery. The purpose of the PhD thesis was: To indentify the number of EA, the causative diagnosis and the indication for surgical removal of the eye, the chosen surgical technique and to evaluate a possible change in surgical technique in Denmark from 1996 until 2003 (paper I); To describe the phantom eye syndrome and its prevalence of visual hallucinations, phantom pain and phantom sensations (paper II); To characterise the quality of phantom eye pain, including its intensity and frequency among EA patients. We attempted to identify patients with increased risk of developing pain after EA and investigated if preoperative pain is a risk factor for a later development of phantom pain (paper III); In addition we wanted to investigate the health related quality of life, perceived stress, self rated health, job separation due to illness or disability and socio-economic position of the EA in comparison with the general Danish population (paper IV). The studies were based on: Records on 431 EA patients, clinical ophthalmological examination and an interview study of 173 EA patients and a questionnaire answered by 120 EA patients. Conclusions: The most frequent indications for EA in Denmark were painful blind eye (37%) and neoplasm (34%). During the study period 1996-2003, the annual number of eye amputations was stable, but an increase in bulbar eviscerations was noticed. Orbital implants were used with an increasing tendency until 2003. The Phantom eye syndrome is frequent among EA patients. Visual hallucinations were described by 42% of the patients. The content were mainly elementary visual hallucinations, with white or colored light as a continuous sharp light or as moving dots. The most frequent triggers were darkness, closing of the eyes, fatigue and psychological stress. Fifty-four percent of the patients had visual hallucinations more than once a week. Ten patients were so visually disturbed that it interfered with their daily life. Approximately 23% of all EA experience phantom pain for several years after the surgery. Phantom pain was reported to be of three different qualities: (i) cutting, penetrating, gnawing or oppressive (n = 19); (ii) radiating, zapping or shooting (n = 8); (iii) superficial burning or stinging (n = 5); or a mixture of these different pain qualities (n = 7). The median intensity on a visual analogue scale, ranging from 0 to 100, was 36 [range: 1-89]. One-third of the patients experienced phantom pain every day. Chilliness, windy weather and psychological stress/fatigue were the most commonly reported triggers for pain. Factors associated with phantom pain were: ophthalmic pain before EA, the presence of implant and a patient reported high degree of conjunctival secretion. A common reason for EA is the presence of a painful blind eye. However, one third of these patients continue to have pain after the EA. Phantom sensations were present in 2% of the patients. The impact of an eye amputation is considerable. EA patients have poorer health related quality of life, poorer self-rated health and more perceived stress than does the general population. The largest differences in health related quality of life between the EA patients and the general population were related to role limitations due to emotional problems and mental health. Patients with the indication painful blind eye are having lower scores in all aspects of health related quality of life and perceived stress than patients with the indication neoplasm and trauma. The percentage of eye amputated which is divorced or separated was twice as high as in the general population. Furthermore, 25% retired or changed to part-time jobs due to eye disease and 39.5% stopped participating in leisure activities due to their EAs. © 2010 Acta Ophthalmologica Scandinavica Foundation.


Busch A.,Copenhagen University | Hippler M.,University of Munster
Biochimica et Biophysica Acta - Bioenergetics | Year: 2011

Eukaryotic photosystem I consists of two functional moieties: the photosystem I core, harboring the components for the light-driven charge separation and the subsequent electron transfer, and the peripheral light-harvesting complex (LHCI). While the photosystem I-core remained highly conserved throughout the evolution, with the exception of the oxidizing side of photosystem I, the LHCI complex shows a high degree of variability in size, subunits composition and bound pigments, which is due to the large variety of different habitats photosynthetic organisms dwell in. Besides summarizing the most current knowledge on the photosystem I-core structure, we will discuss the composition and structure of the LHCI complex from different eukaryotic organisms, both from the red and the green clade. Furthermore, mechanistic insights into electron transfer between the donor and acceptor side of photosystem I and its soluble electron transfer carrier proteins will be given. This article is part of a Special Issue entitled: Regulation of Electron Transport in Chloroplasts. © 2010 Published by Elsevier B.V.


Smed S.,Copenhagen University
Nutrition Bulletin | Year: 2012

This paper summarises the recently introduced fat tax in Denmark, which came into force on 1 October 2012, and discusses some of the consequences of introducing the tax. Furthermore, this paper discusses the theoretical background and reasoning for imposing a fat tax as well as some of the problems and concerns stated, especially by the food industry. The fat tax is a tax paid per kilogram of saturated fat in the following foods if the content of saturated fat exceeds 2.3g/100g. These include meat, dairy products and animal fats that are rendered or are extracted in other ways, edible oils and fats, margarine and spreadable blended spreads. The declared aim of the tax is to reduce the consumption of saturated fat among the Danish population in order to decrease the prevalence of diet-related illnesses. The tax is part of a larger reform of the Danish tax system with the general aim of decreasing the income taxation pressure and financing it by, among other things, increased environmental and energy taxes, as well as increased 'health' taxes. Pre-tax simulations predict that the health tax on saturated fat will give rise to a reduction in the consumption of saturated fat of approximately 8%. © 2012 The Author. Journal compilation © 2012 British Nutrition Foundation.


Pasgaard M.,Copenhagen University
Environmental Impact Assessment Review | Year: 2013

Reduced Emissions from Deforestation and Forest Degradation in developing countries (REDD. +) has moved to the central stage of the climate change debate by being promoted as a significant, cheap, and quick win-win strategy to reduce greenhouse gas emissions and thereby mitigate climate change. In order to be successful in reducing emissions while providing the projected social and environmental co-benefits, REDD. + needs to overcome key challenges of insecure forest tenure and inequity in the distribution of benefits. Such challenges threaten to affect the livelihoods and well-being in the local communities and in turn the effectiveness of REDD+. While REDD. + programs will affect the participating communities, there is limited knowledge as to what social impacts these projects may bring to the local population. Similarly, assessment of these social dimensions has received little attention until recently, and is consequently out of sync with the realities of REDD. + projects.The present paper aims to shed light on the methodological and contextual challenges in the assessment of the social dimensions of REDD+. Some of the main social concerns of REDD. + are outlined with an emphasis on the uniqueness and complexity of REDD. + interventions. Recently proposed approaches to assess social impacts in REDD. + are critically assessed in terms of the diversity of frameworks proposed, choice of social indicators, and data collection requirements. Specifically, these methodological implications are further discussed in the light of the social dimensions and the prescribed regulations of REDD. + in a Cambodian context. © 2012 Elsevier Inc.


Bonde J.P.E.,Copenhagen University
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2013

Purpose of review: To highlight and discuss the new evidence on occupational and environmental risk to male reproductive function. Recent findings: Semen quality following occupational exposure to boron (an acknowledged experimental reproductive toxicant) and benzene, and new evidence on low-level environmental exposure to widespread xenobiotics with endocrine actions. Summary: The naturally occurring semimetal boron is an experimental reproductive toxicant, but now a Turkish semen study corroborates earlier evidence that high-level occupational exposure is not toxic to human spermatogenesis. It seems that human exposure levels are below the levels that cause reproductive toxicity in rodents. On the contrary, there is now ample evidence that the carcinogenic substance benzene may cause chromosomal aberrations in sperm at very low exposure levels. This includes chromosomal deletions that are known to cause infertility, mental retardation and congenital malformations. This research highlights the need to scrutinize the chemicals for possible male-mediated developmental toxicity. Several occupational studies are addressing adult testicular function in men exposed to chemicals that may interfere with endocrine signalling such as bisphenol A and phthalates, but findings are rather inconsistent and it remains to be established whether these widespread chemicals have any impact on male fertility. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Darwin Murrell K.,Copenhagen University | Pozio E.,Istituto Superiore di Sanita
Emerging Infectious Diseases | Year: 2011

To assess the global incidence and clinical effects of human trichinellosis, we analyzed outbreak report data for 1986-2009. Searches of 6 international databases yielded 494 reports. After applying strict criteria for relevance and reliability, we selected 261 reports for data extraction. From 1986 through 2009, there were 65,818 cases and 42 deaths reported from 41 countries. The World Health Organization European Region accounted for 87% of cases; 50% of those occurred in Romania, mainly during 1990-1999. Incidence in the region ranged from 1.1 to 8.5 cases per 100,000 population. Trichinellosis affected primarily adults (median age 33.1 years) and about equally affected men (51%) and women. Major clinical effects, according to 5,377 well-described cases, were myalgia, diarrhea, fever, facial edema, and headaches. Pork was the major source of infection; wild game sources were also frequently reported. These data will be valuable for estimating the illness worldwide.


Kessing L.V.,Copenhagen University
Current Opinion in Psychiatry | Year: 2012

Purpose of Review: Depression is associated with increased risk of subsequent development of dementia; however, the nature of the association is still poorly understood. The purpose of the review was based on recent studies to discuss whether depression is a prodromal state of dementia or an independent risk factor for dementia, as well as to discuss how the type of depression, the type of dementia, and antidepressant treatment influence the association. Recent Findings: Findings from recent studies suggest that some forms of depressive illness, for example early-onset depression before age 65 years and recurrent depression, may constitute long-term risk factors for development of dementia, whereas the onset of more recent depressive symptoms may reflect a prodromal phase of dementia. It is not clear whether specific subtypes of depression correspond to specific types of dementia. Recent studies suggest that long-term treatment with antidepressants may decrease the risk of developing some types of dementia, depending on the type of depressive disorder. Summary: This review has shown that the type of depression and dementia, as well as the effect of drug treatment, has to be considered to improve knowledge on the association between depression and dementia. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Groenning M.,Copenhagen University | Groenning M.,Linkoping University
Journal of Chemical Biology | Year: 2010

Because understanding amyloid fibrillation in molecular detail is essential for development of strategies to control amyloid formation and overcome neurodegenerative disorders, increased understanding of present molecular probes as well as development of new probes are of utmost importance. To date, the binding modes of these molecular probes to amyloid fibrils are by no means adequately described or understood, and the large number of studies on Thioflavin T (ThT) and Congo Red (CR) binding have resulted in models that are incomplete and conflicting. Different types of binding sites are likely to be present in amyloid fibrils with differences in binding modes. ThT may bind in channels running parallel to the long axis of the fibril. In the channels, ThT may bind in either a monomeric or dimeric form of which the molecular conformation is likely to be planar. CR may bind in grooves formed along the β-sheets as a planar molecule in either a monomeric or supramolecular form. © 2009 Springer-Verlag.


Over the 20th century, the frequent use of nickel in consumer products resulted in an increasing prevalence of nickel allergy. Risk items included suspenders in the 1950s-1960s; buttons, zippers and rivets in the 1970s; and ear-piercing jewellery in the 1980s. When subjects allergic to nickel were exposed to nickel in high concentrations, it often resulted in allergic nickel contact dermatitis and hand eczema. In 1990, the Danish government began to regulate consumer nickel exposure as a response to the increasing nickel allergy problem. In 1994, the EU Nickel Directive was passed, a regulation that was based on the Danish and Swedish nickel regulations. These major public health interventions were expected to change the epidemiology of nickel allergy and dermatitis in Europe. Furthermore, it was debated whether nickel would be replaced by cobalt in inexpensive jewellery and result in higher prevalence of cobalt allergy. An evaluation of the possible effects of the European nickel regulations is of importance to ensure protection of consumers and dermatitis patients. This doctoral thesis aimed to evaluate the effects of regulatory interventions on nickel exposure by investigating the development of nickel allergy and dermatitis before and after nickel regulation. Furthermore, a change in the association between nickel allergy and hand eczema was evaluated. The nickel spot test was validated to determine its value when used for screening purposes. Possible explanations for the persistence of nickel allergy were explored including genetic predisposition and consumer nickel exposure from jewellery and accessories. A cobalt spot test was developed and validated. Finally, it was evaluated whether a cobalt allergy epidemic had replaced the nickel allergy epidemic after nickel regulation in terms of increasing cobalt sensitization and cobalt exposure. The thesis showed that the prevalence of nickel allergy decreased significantly after nickel regulation in young Danish women from the general population (18-35 years) and in young Danish female dermatitis patients from a university patch test clinic (0-30 years). Stratification by ear-piercing status revealed that women ear pierced before 1990 had a significantly higher prevalence of nickel allergy and dermatitis than women ear pierced after 1990. Furthermore, the association between hand eczema and nickel allergy decreased in young women aged 18-35 years when a comparison was made between women who were patch tested and questioned in, respectively, 1990 and 2006. Despite the decreasing prevalence of nickel allergy, this condition remains prevalent in young Danish women, as about 10% are nickel allergic. Genetic predisposition to nickel allergy was evaluated by investigating the possible association between filaggrin null mutation status and nickel allergy. A positive association was found but it was also concluded that environmental nickel exposure is of much greater importance. Thus, of 354 consumer items purchased from 36 different stores in Copenhagen, 22% released nickel in concentrations that may result in nickel dermatitis in sensitized subjects. Therefore excessive consumer nickel exposure remains common in Denmark and may be an important explanation for the persistence of nickel allergy. Excessive nickel release was also frequent when samples of earrings purchased in Warsaw and London were examined with the nickel spot test, in particular earrings purchased from street markets and shops with independent ownership. Only very weak indications of an emerging cobalt allergy epidemic were found, as the prevalence of cobalt allergy has not yet increased in young people and only four of 354 consumer items purchased in Copenhagen released cobalt in concentrations that may result in cobalt dermatitis in sensitized individuals. The specificity of the nickel spot test was 98% and the sensitivity 59%. Also, a cobalt spot test was developed and validated and seemed to be a useful diagnostic tool. In conclusion, the Danish nickel regulation and the EU Nickel Directive have changed the epidemiology of nickel allergy in Denmark. However, the Nickel Directive and its reference methods need to be revised to better protect consumers and dermatitis patients. © 2011 John Wiley & Sons A/S.


Open3DQSAR is a freely available open-source program aimed at chemometric analysis of molecular interaction fields. MIFs can be imported from different sources (GRID, CoMFA/CoMSIA, quantum-mechanical electrostatic potential or electron density grids) or generated by Open3DQSAR itself. Much focus has been put on automation through the implementation of a scriptable interface, as well as on high computational performance achieved by algorithm parallelization. Flexibility and interoperability with existing molecular modeling software make Open3DQSAR a powerful tool in pharmacophore assessment and ligand-based drug design. © 2010 Springer-Verlag.


This study was aimed at identifying genomic regions controlling feeding behavior in Danish Duroc boars and its potential implications for eating behavior in humans. Data regarding individual daily feed intake (DFI), total daily time spent in feeder (TPD), number of daily visits to feeder (NVD), average duration of each visit (TPV), mean feed intake per visit (FPV) and mean feed intake rate (FR) were available for 1130 boars. All boars were genotyped using the Illumina Porcine SNP60 BeadChip. The association analyses were performed using the GenABEL package in the R program. Sixteen SNPs were found to have moderate genome-wide significance (p<5E-05) and 76 SNPs had suggestive (p<5E-04) association with feeding behavior traits. MSI2 gene on chromosome (SSC) 14 was very strongly associated with NVD. Thirty-six SNPs were located in genome regions where QTLs have previously been reported for behavior and/or feed intake traits in pigs. The regions: 64-65 Mb on SSC 1, 124-130 Mb on SSC 8, 63-68 Mb on SSC 11, 32-39 Mb and 59-60 Mb on SSC 12 harbored several signifcant SNPs. Synapse genes (GABRR2, PPP1R9B, SYT1, GABRR1, CADPS2, DLGAP2 and GOPC), dephosphorylation genes (PPM1E, DAPP1, PTPN18, PTPRZ1, PTPN4, MTMR4 and RNGTT) and positive regulation of peptide secretion genes (GHRH, NNAT and TCF7L2) were highly significantly associated with feeding behavior traits. This is the first GWAS to identify genetic variants and biological mechanisms for eating behavior in pigs and these results are important for genetic improvement of pig feed efficiency. We have also conducted pig-human comparative gene mapping to reveal key genomic regions and/or genes on the human genome that may influence eating behavior in human beings and consequently affect the development of obesity and metabolic syndrome. This is the first translational genomics study of its kind to report potential candidate genes for eating behavior in humans.


Watson D.,Copenhagen University | Jakobsson P.,University of Iceland
Astrophysical Journal | Year: 2012

The afterglows of gamma-ray bursts (GRBs) have more soft-X-ray absorption than expected from the foreground gas column in the Galaxy. While the redshift of the absorption can in general not be constrained from current X-ray observations, it has been assumed that the absorption is due to metals in the host galaxy of the GRB. The large sample of X-ray afterglows and redshifts now available allows the construction of statistically meaningful distributions of the metal column densities. We construct such a sample and show, as found in previous studies, that the typical absorbing column density (NHX) increases substantially with redshift, with few high column density objects found at low-to-moderate redshifts.We show, however, that when highly extinguished bursts are included in the sample, using redshifts from their host galaxies, high column density sources are also found at low-to-moderate redshift.We infer from individual objects in the sample and from observations of blazars that the increase in column density with redshift is unlikely to be related to metals in the intergalactic medium or intervening absorbers. Instead we show that the origin of the apparent increase with redshift is primarily due to dust extinction bias: GRBs with high X-ray absorption column densities found at z ≲ 4 typically have very high dust extinction column densities, while those found at the highest redshifts do not. It is unclear how such a strongly evolving NHX/AV ratio would arise, and based on current data, remains a puzzle. © 2012. The American Astronomical Society. All rights reserved. Printed in the U.S.A.


By combining state-of-the-art approaches in ancient genomics, Meyer and co-workers have reconstructed the mitochondrial sequence of an archaic hominin that lived at Sierra de Atapuerca, Spain about 400,000 years ago. This achievement follows recent advances in molecular anthropology that delivered the genome sequence of younger archaic hominins, such as Neanderthals and Denisovans. Molecular phylogenetic reconstructions placed the Atapuercan as a sister group to Denisovans, although its morphology suggested closer affinities with Neanderthals. In addition to possibly challenging our interpretation of the fossil record, this study confirms that genomic information can be recovered from extremely damaged DNA molecules, even in the presence of significant levels of human contamination. Together with the recent characterization of a 700,000-year-old horse genome, this study opens the Middle Pleistocene to genomics, thereby extending the scope of ancient DNA to the last million years. © 2014 WILEY Periodicals, Inc.


Ojanen T.,Aalto University | Borkje K.,Copenhagen University
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2014

We present a scheme for cooling mechanical motion to the ground state in an optomechanical system. Unlike standard sideband cooling, this scheme applies to the so-called unresolved sideband regime, where the resonance frequency of the mechanical mode is much smaller than the cavity linewidth. Ground-state cooling becomes possible when assuming the presence of an additional, auxiliary mechanical mode and exploiting the effect of optomechanically induced transparency. We first consider a system where one optical cavity interacts with two mechanical modes and show that ground-state cooling of the unresolved mechanical mode is possible when the auxiliary mode is in the resolved sideband regime. We then present a modified setup involving two cavity modes, where both mechanical modes are allowed to be in the unresolved sideband regime. © 2014 American Physical Society.


Park S.,Yonsei University | Gildersleeve J.C.,U.S. National Cancer Institute | Blixt O.,Copenhagen University | Shin I.,Yonsei University
Chemical Society Reviews | Year: 2013

In the last decade, carbohydrate microarrays have been core technologies for analyzing carbohydrate-mediated recognition events in a high-throughput fashion. A number of methods have been exploited for immobilizing glycans on the solid surface in a microarray format. This microarray-based technology has been widely employed for rapid analysis of the glycan binding properties of lectins and antibodies, the quantitative measurements of glycan-protein interactions, detection of cells and pathogens, identification of disease-related anti-glycan antibodies for diagnosis, and fast assessment of substrate specificities of glycosyltransferases. This review covers the construction of carbohydrate microarrays, detection methods of carbohydrate microarrays and their applications in biological and biomedical research. © 2013 The Royal Society of Chemistry.


Andersen P.K.,Copenhagen University
Statistics in Medicine | Year: 2013

We study the competing risks model and show that the cause j cumulative incidence function integrated from 0 to τ has a natural interpretation as the expected number of life years lost due to cause j before time τ. This is analogous to the τ-restricted mean lifetime, which is the survival function integrated from 0 to τ. It is discussed how the number of years lost may be related to subject-specific explanatory variables in a regression model based on pseudo-observations, and the method is exemplified using data from a bone marrow transplantation study. Finally, inclusion of standard mortality rates is discussed. © 2013 John Wiley & Sons, Ltd.


Mobjerg N.,Copenhagen University
Acta physiologica (Oxford, England) | Year: 2011

Tardigrades are microscopic animals found worldwide in aquatic as well as terrestrial ecosystems. They belong to the invertebrate superclade Ecdysozoa, as do the two major invertebrate model organisms: Caenorhabditis elegans and Drosophila melanogaster. We present a brief description of the tardigrades and highlight species that are currently used as models for physiological and molecular investigations. Tardigrades are uniquely adapted to a range of environmental extremes. Cryptobiosis, currently referred to as a reversible ametabolic state induced by e.g. desiccation, is common especially among limno-terrestrial species. It has been shown that the entry and exit of cryptobiosis may involve synthesis of bioprotectants in the form of selective carbohydrates and proteins as well as high levels of antioxidant enzymes and other free radical scavengers. However, at present a general scheme of mechanisms explaining this phenomenon is lacking. Importantly, recent research has shown that tardigrades even in their active states may be extremely tolerant to environmental stress, handling extreme levels of ionizing radiation, large fluctuation in external salinity and avoiding freezing by supercooling to below -20 °C, presumably relying on efficient DNA repair mechanisms and osmoregulation. This review summarizes the current knowledge on adaptations found among tardigrades, and presents new data on tardigrade cell numbers and osmoregulation. © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society.


Hoffmann E.K.,Copenhagen University
Acta physiologica (Oxford, England) | Year: 2011

Cell volume homeostasis and its fine-tuning to the specific physiological context at any given moment are processes fundamental to normal cell function. The understanding of cell volume regulation owes much to August Krogh, yet has advanced greatly over the last decades. In this review, we outline the historical context of studies of cell volume regulation, focusing on the lineage started by Krogh, Bodil Schmidt-Nielsen, Hans-Henrik Ussing, and their students. The early work was focused on understanding the functional behaviour, kinetics and thermodynamics of the volume-regulatory ion transport mechanisms. Later work addressed the mechanisms through which cellular signalling pathways regulate the volume regulatory effectors or flux pathways. These studies were facilitated by the molecular identification of most of the relevant channels and transporters, and more recently also by the increased understanding of their structures. Finally, much current research in the field focuses on the most up- and downstream components of these paths: how cells sense changes in cell volume, and how cell volume changes in turn regulate cell function under physiological and pathophysiological conditions. © 2010 The Authors. Acta Physiologica © 2010 Scandinavian Physiological Society.


Skovso S.,Copenhagen University
Journal of Diabetes Investigation | Year: 2014

The pathology of type 2 diabetes is complex, with multiple stages culminating in a functional β-cell mass that is insufficient to meet the body's needs. Although the broad outlines of the disease etiology are known, many critical questions remain to be answered before next-generation therapeutics can be developed. In order to further elucidate the pathobiology of this disease, animal models mimicking the pathology of human type 2 diabetes are of great value. One example of a type 2 diabetes animal model is the high-fat diet-fed, streptozotocin (HFD/STZ)-treated rat model. The present review first summarizes the current understanding of the metabolic profile and pathology involved in the different stages of the type 2 diabetes disease progression in humans. Second, the known characteristics of the HFD/STZ rat model are reviewed and compared with the pathophysiology of human type 2 diabetes. Next, the suitability of the HFD/STZ model as a model of type 2 diabetes with a focus on identifying critical caveats and unanswered questions about the model is discussed. The improved understanding of refined animal models will hopefully lead to more relevant preclinical studies and development of improved therapeutics for diabetes. Depending on the amount of residual functional β-cells mass, the HFD/STZ rat model might be a suitable animal model of the final stage of type 2 diabetes. This review thoroughly discusses the group of type 2 diabetes rat models employing a combination of high fat diet and streptozotocin, and in particular how they compare to the pathophysiology of human diabetes. Practical advice for the use and interpretation of this model is presented. © 2014 The Author.


Aanaes H.,Technical University of Denmark | Dahl A.L.,Technical University of Denmark | Pedersen K.S.,Copenhagen University
International Journal of Computer Vision | Year: 2012

Not all interest points are equally interesting. The most valuable interest points lead to optimal performance of the computer vision method in which they are employed. But a measure of this kind will be dependent on the chosen vision application. We propose a more general performance measure based on spatial invariance of interest points under changing acquisition parameters by measuring the spatial recall rate. The scope of this paper is to investigate the performance of a number of existing well-established interest point detection methods. Automatic performance evaluation of interest points is hard because the true correspondence is generally unknown. We overcome this by providing an extensive data set with known spatial correspondence. The data is acquired with a camera mounted on a 6-axis industrial robot providing very accurate camera positioning. Furthermore the scene is scanned with a structured light scanner resulting in precise 3D surface information. In total 60 scenes are depicted ranging from model houses, building material, fruit and vegetables, fabric, printed media and more. Each scene is depicted from 119 camera positions and 19 individual LED illuminations are used for each position. The LED illumination provides the option for artificially relighting the scene from a range of light directions. This data set has given us the ability to systematically evaluate the performance of a number of interest point detectors. The highlights of the conclusions are that the fixed scale Harris corner detector performs overall best followed by the Hessian based detectors and the difference of Gaussian (DoG). The methods based on scale space features have an overall better performance than other methods especially when varying the distance to the scene, where especially FAST corner detector, Edge Based Regions (EBR) and Intensity Based Regions (IBR) have a poor performance. The performance of Maximally Stable Extremal Regions (MSER) is moderate. We observe a relatively large decline in performance with both changes in viewpoint and light direction. Some of our observations support previous findings while others contradict these findings. © 2011 Springer Science+Business Media, LLC.


Borkje K.,Copenhagen University
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2014

We present a generic quantum master equation whose dissipative dynamics autonomously stabilizes a harmonic oscillator in the n=1 Fock state. A multimode optomechanical system is analyzed and shown to be an example of a physical system obeying this model. We show that the optomechanical setup enables preparation of a mechanical oscillator in a nonclassical steady state, and that this state indeed approaches a single phonon Fock state in the ideal parameter regime. The generic model may be useful in other settings, such as cavity or circuit quantum electrodynamics or trapped ion physics. © 2014 American Physical Society.


Twetman S.,Copenhagen University
Advances in dental research | Year: 2012

Modulation of the microbiota for restoring and maintaining health is a growing issue in medical science. A search for relevant clinical trials on the use of probiotic bacteria as a potential and clinically applicable anti-caries measure was performed. According to predetermined criteria, papers were selected and key data on study design, sample size, intervention, duration, and results were extracted. Two animal and 19 human studies were retrieved. Most studies were short-term and restricted to microbiological endpoints, and only 3 human studies reported a caries endpoint. A high degree of heterogeneity among the included investigations hampered the analysis. Significant reductions of mutans streptococci in saliva or plaque following daily intake of probiotic lactobacilli or bifidobacteria were reported in 12 out of 19 papers, whereas 3 reported an increase of lactobacilli. Three caries trials in preschool children and the elderly demonstrated prevented fractions of between 21% and 75% following regular intakes of milk supplemented with L. rhamnosus. No adverse effects or potential risks were reported. The currently available literature does not exclude the possibility that probiotic bacteria can interfere with the oral biofilm, but any clinical recommendation would be premature. Large-scale clinical studies with orally derived specific anti-caries candidates are still lacking.


Bacterial cells monitor their environment by sensing a set of signals. Typically, these environmental signals affect promoter activities by altering the activity of transcription regulatory proteins. Promoters are often regulated by more than one regulatory protein, and in these cases the relevant signals are integrated by certain logic. In this work, we study how single amino acid substitutions in a regulatory protein (GalR) affect transcriptional regulation and signal integration logic at a set of engineered promoters. Our results suggest that point mutations in regulatory genes allow independent evolution of regulatory logic at different promoters. © 2014 Semsey.


Hjorth J.,Copenhagen University
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2013

The observed association between supernovae and gamma-ray bursts represents a cornerstone in our understanding of the nature of gamma-ray bursts. The collapsar model provides a theoretical framework for this connection. A key element is the launch of a bipolar jet (seen as a gamma-ray burst). The resulting hot cocoon disrupts the star, whereas the 56Ni produced gives rise to radioactive heating of the ejecta, seen as a supernova. In this discussion paper, I summarize the observational status of the supernova- gamma-ray burst connection in the context of the 'engine' picture of jet-driven supernovae and highlight SN2012bz/GRB 120422A-with its luminous supernova but intermediate high-energy luminosity- as a possible transition object between low-luminosity and jet gamma-ray bursts. The jet channel for supernova explosions may provide new insights into supernova explosions in general. © 2013 The Author(s) Published by the Royal Society. All rights reserved.


Thorup M.,Copenhagen University
Proceedings - Annual IEEE Symposium on Foundations of Computer Science, FOCS | Year: 2013

Simple tabulation dates back to Zobrist in 1970 who used it for game playing programs. Keys are viewed as consisting of c characters from some alphabet Φ. We initialize c tables h0, ... , hc-1 mapping characters to random hash values. A key x = (x0, ... , x c-1) is hashed to h0[x0]⊕...⊕hc-1[xc-1], where ⊕ denotes bit-wise exclusive-or. The scheme is extremely fast when the character hash tables hi are in cache. Simple tabulation hashing is not even 4-independent, but we show here that if we apply it twice, then we do get high independence. First we hash to some intermediate keys that are 6 times longer than the original keys, and then we hash the intermediate keys to the final hash values. The intermediate keys have d = 6c characters from Φ. We can then view the hash function as a highly unbalanced bipartite graph with keys on one side, each with edges to d output characters on the other side. We show that this graph has nice expansion properties, and from that it follows that if we perform another level of simple tabulation on the intermediate keys, then the composition is a highly independent hash function. More precisely, the independence we get is ΦΩ(1/c). In our O-notation, we view both Φ and c is going to infinity, but with c much smaller than Φ. Our space is O(cΦ) and the hash function is evaluated in O(c) time. Siegel [FOCS'89, SICOMP'04] has proved that with this space, if the hash function is evaluated in o(c) time, then the independence can only be o(c), so our evaluation time is best possible for Ω(c) independence-our independence is much higher if c = Φo(1/c). Siegel used O(c)c evaluation time to get the same independence with similar space. Siegel's main focus was c = O(1), but we are exponentially faster when c = ω(1). Applying our scheme recursively, we can increase our independence to ΦΩ(1) with o(clog c) evaluation time. Compared with Siegel's scheme this is both faster and higher independence. Siegel states about his scheme that it is "far too slow for any practical application". Our scheme is trivial to implement, and it does provide realistic implementations of 100-independent hashing for, say, 32-bit and 64-bit keys. Copyright © 2013 by The Institute of Electrical and Electronics Engineers, Inc.


Vinther J.,University of Bristol | Stein M.,Copenhagen University | Longrich N.R.,University of Bath | Harper D.A.T.,Durham University
Nature | Year: 2014

Large, actively swimming suspension feeders evolved several times in Earth's history, arising independently from groups as diverse as sharks, rays and stemteleost fishes1, and in mysticete whales2. However, animals occupying this niche have not been identified fromthe early Palaeozoic era. Anomalocarids, a group of stem arthropods that were the largest nektonic animals of the Cambrian and Ordovician periods, are generally thought to have been apex predators3-5. Here we describe new material from Tamisiocaris borealis6, an anomalocarid fromthe EarlyCambrian (Series 2) Sirius Passet Fauna of North Greenland, and propose that its frontal appendage is specialized for suspension feeding. The appendage bears long, slender and equally spaced ventral spines furnished with dense rows of long and fine auxiliary spines. This suggests that T. borealiswas a microphagous suspension feeder, using its appendages for sweep-net capture of food items down to 0.5mm, within the size range of mesozooplankton such as copepods. Our observations demonstrate that large, nektonic suspension feeders first evolvedduring theCambrian explosion, as part of an adaptive radiation of anomalocarids. The presence of nektonic suspension feeders intheEarlyCambrian, togetherwith evidence for a diverse pelagic community containing phytoplankton7,8 andmesozooplankton7,9,10, indicate the existence of a complex pelagic ecosystem11 supported by high primary productivity and nutrient flux12,13. Cambrian pelagic ecosystems seem to have been more modern than previously believed. © 2014 Macmillan Publishers Limited.


Holst A.G.,University Hospital Rigshospitalet | Jensen G.,Hvidovre University Hospital | Prescott E.,Copenhagen University
Circulation | Year: 2010

BACKGROUND-: Studies have suggested a link between risk factors for atherosclerotic disease and venous thromboembolism (VTE), but results are heterogeneous. We sought to identify risk factors for VTE with a focus on risk factors for atherosclerotic disease. METHODS AND RESULTS-: Data were taken from the Copenhagen City Heart Study, a prospective cohort study of a random, age-stratified sample of people living in a defined area in Copenhagen, Denmark, started in 1976 with follow-up until 2007. First VTE (deep vein thrombosis and pulmonary embolism) diagnosis was retrieved from electronic national registries from study baseline to 2007. Of 18 954 subjects (median follow-up, 19.5 years) representing 360 399 person-years of follow-up, 969 subjects experienced at least 1 VTE, corresponding to a crude incidence rate of 2.69 (95% confidence interval [CI], 2.52 to 2.86) per 1000 person-years. The variables found to be significantly associated with VTE in a multivariable model adjusted for age and calendar time were as follows: body mass index (hazard ratio [HR] for ≥35 versus <20=2.10 [95% CI, 1.39 to 3.16]); smoking (HR for ≥25 g tobacco per day versus never smoker=1.52 [95% CI, 1.15 to 2.01]); gender (HR for men versus women=1.24 [95% CI, 1.08 to 1.42]); household income (HR for medium versus low=0.82 [95% CI, 0.70 to 0.95]); and diastolic blood pressure (HR for >100 versus <80 mm Hg=1.34 [95% CI, 1.08 to 1.66]). Other cardiovascular risk factors including total/high-density lipoprotein/low-density lipoprotein cholesterol levels, triglyceride levels, and diabetes mellitus were not associated with VTE. CONCLUSIONS-: Obesity and smoking were both found to be important risk factors for VTE whereas total/high-density lipoprotein/low- density lipoprotein cholesterol levels, triglyceride levels, and diabetes mellitus were not. © 2010 American Heart Association, Inc.


Miravalle A.,University of Colorado at Denver | Jensen R.,Copenhagen University | Kinkel R.P.,Beth Israel Deaconess Medical Center
Archives of Neurology | Year: 2011

Objective: To assess clinical consequences of temporary natalizumab dosage suspension. Design: Prospective cohort study. Setting: Multiple sclerosis (MS) center at an academic medical center in the United States. Patients: Thirty-two patients with MS who had received at least 12 consecutive natalizumab infusions. Main Outcomes Measures: Recurrent MS disease activity, defined as a clinically documented exacerbation with objective findings and/or the development of 1 or more new gadolinium-enhancing lesions on magnetic resonance imaging. Results: Thirty-eight percent of patients with relapsing-remitting and secondary progressive MS experienced relapses during therapy interruption or shortly after restarting natalizumab therapy (9 of 24 and 3 of 8, respectively), but relapses were severe with unusually widespread evidence of inflammatory activity on magnetic resonance imaging in several patients with secondary progressive MS with greater inflammatory disease activity prior to starting natalizumab therapy. Imaging and cerebrospinal fluid findings in these cases were suggestive of an immune reconstitution inflammatory syndrome. Overall, relapses occurred more often in younger patients with fewer natalizumab infusions prior to therapy interruption. The number of gadolinium-enhancing lesions at the time of relapse after therapy interruption was modestly correlated with the number of gadolinium-enhancing lesions prior to starting natalizumab therapy (r=0.51; P=.45). Prior disease control resumed after reinstitution of natalizumab therapy in all patients. Conclusions: In this cohort of patients with MS who had disease refractive to multiple therapeutics before starting natalizumab treatment, magnetic resonance imaging and clinical disease activity returned, often aggressively, following discontinuation of natalizumab therapy. These findings suggest we should consider strategies to minimize the risk of immune reconstitution inflammatory syndrome after natalizumab discontinuation. ©2011 American Medical Association. All rights reserved.


Evidence shows that antioxidant supplements may increase mortality. Our aims were to assess whether different doses of beta-carotene, vitamin A, and vitamin E affect mortality in primary and secondary prevention randomized clinical trials with low risk of bias. The present study is based on our 2012 Cochrane systematic review analyzing beneficial and harmful effects of antioxidant supplements in adults. Using random-effects meta-analyses, meta-regression analyses, and trial sequential analyses, we examined the association between beta-carotene, vitamin A, and vitamin E, and mortality according to their daily doses and doses below and above the recommended daily allowances (RDA). We included 53 randomized trials with low risk of bias (241,883 participants, aged 18 to 103 years, 44.6% women) assessing beta-carotene, vitamin A, and vitamin E. Meta-regression analysis showed that the dose of vitamin A was significantly positively associated with all-cause mortality. Beta-carotene in a dose above 9.6 mg significantly increased mortality (relative risk (RR) 1.06, 95% confidence interval (CI) 1.02 to 1.09, I(2) = 13%). Vitamin A in a dose above the RDA (> 800 μg) did not significantly influence mortality (RR 1.08, 95% CI 0.98 to 1.19, I(2) = 53%). Vitamin E in a dose above the RDA (> 15 mg) significantly increased mortality (RR 1.03, 95% CI 1.00 to 1.05, I(2) = 0%). Doses below the RDAs did not affect mortality, but data were sparse. Beta-carotene and vitamin E in doses higher than the RDA seem to significantly increase mortality, whereas we lack information on vitamin A. Dose of vitamin A was significantly associated with increased mortality in meta-regression. We lack information on doses below the RDA. All essential compounds to stay healthy cannot be synthesized in our body. Therefore, these compounds must be taken through our diet or obtained in other ways [1]. Oxidative stress has been suggested to cause a variety of diseases [2]. Therefore, it is speculated that antioxidant supplements could have a potential role in preventing diseases and death. Despite the fact that a normal diet in high-income countries may provide sufficient amounts of antioxidants [3,4], more than one third of adults regularly take antioxidant supplements [5,6].


James J.B.,Copenhagen University
Astrophysical Journal | Year: 2012

We report a technique to calculate the impact of distinct physical processes inducing non-Gaussianity on the cosmological density field. A natural decomposition of the cosmic genus statistic into an orthogonal polynomial sequence allows complete expression of the scale-dependent evolution of the topology of large-scale structure, in which effects including galaxy bias, nonlinear gravitational evolution, and primordial non-Gaussianity may be delineated. The relationship of this decomposition to previous methods for analyzing the genus statistic is briefly considered and the following applications are made: (1) the expression of certain systematics affecting topological measurements, (2) the quantification of broad deformations from Gaussianity that appear in the genus statistic as measured in the Horizon Run simulation, and (3) the study of the evolution of the genus curve for simulations with primordial non-Gaussianity. These advances improve the treatment of flux-limited galaxy catalogs for use with this measurement and further the use of the genus statistic as a tool for exploring non-Gaussianity. © 2012. The American Astronomical Society. All rights reserved.


Whyte S.R.,Copenhagen University
Anthropology and Medicine | Year: 2012

This paper proposes a way of framing the study of noncommunicable diseases within the more general area of chronic conditions. Focusing on Africa, it takes as points of departure the situation in Uganda, and the approach to health issues developed by a group of European and African colleagues over the years. It suggests a pragmatic analysis that places people's perceptions and practices within a field of possibilities shaped by policy, health care systems, and life conditions. In this field, the dimensions of chronicity and control are the distinctive analytical issues. They lead on to consideration of patterns of sociality related to chronic conditions and their treatment. © 2012 Taylor & Francis.


Mohr S.,Copenhagen University
Anthropology and Medicine | Year: 2014

This paper, analyzing interviews with men that donate their semen in Denmark, explores what it means to be a sperm donor. Breaking with the assumption that men have a specific and clearly identifiable motivation to become sperm donors, this paper leaves the confinement of such an accountable actor model implied in asking for men's motivations to donate semen. Instead, the author describes the experiences of sperm donors to show how the moral, organizational, and biomedical-technological context of sperm donation in Denmark makes for enactments of moral selves as well as specific embodiments of masculinity. Instead of looking for motivations that can be accounted for, the author engages with the question of how donating semen affords men the experience of moral and gendered selves. © 2014 The Author(s). Published by Taylor & Francis.


Nielsen P.E.,Copenhagen University
Current Opinion in Molecular Therapeutics | Year: 2010

Sequence-selective gene targeting constitutes an attractive drug-discovery approach for genetic therapy, with the aim of reducing or enhancing the activity of specific genes at the transcriptional level, or as part of a methodology for targeted gene repair. The pseudopeptide DNA mimic peptide nucleic acid (PNA) can recognize duplex DNA with high sequence specificity and affinity in triplex, duplex and double-duplex invasive modes or non-invasive triplex modes. Novel PNA modification has improved the affinity for DNA recognition via duplex invasion, double-duplex invasion and triplex recognition considerably. Such modifications have also resulted in new approaches to targeted gene repair and sequence-selective double-strand cleavage of genomic DNA. © Thomson Reuters (Scientific) Ltd.


Rehfeld J.F.,Copenhagen University
Regulatory Peptides | Year: 2012

The gut is the largest endocrine organ in the body. Gut hormones share some characteristics: Their structure groups hormones into families, each of which originate from a single gene. A hormone gene is often expressed in multiple peptides due to tandem genes, alternative splicing or differentiated posttranslational processing. By these mechanisms, more than 100 different hormonally active peptides are produced in the gastrointestinal tract. In addition, gut hormones are widely expressed outside the gut. The different cell types often express different products of the same gene and release the peptides in different ways. Consequently, the same peptide may act as a hormone, a local growth factor, or a neurotransmitter. This new biology suggests that gastrointestinal hormones should be conceived as intercellular messengers of major general impact. The following short review is a vignette on steps in the history of gastrointestinal endocrinology from classic studies of digestive juice secretion over peptide chemistry, immunochemistry, and molecular genetics to modern receptor pharmacology and drug development. From shadowy beginnings, gastrointestinal endocrinology has emerged as a central discipline in the understanding of multicellular life and its diseases. © 2012 Elsevier B.V.


Cabel J.F.,Norwegian University of Life Sciences | Oelofse M.,Copenhagen University
Ecology and Society | Year: 2012

Taking departure in the theory of resilience in social-ecological systems, we present an analysis and discussion of how resilience theory can be applied to agroecosystems. Building on the premise that agroecosystems are too complex for resilience to be measured in any precise manner, we delineate behavior-based indicators of resilience within agroecosystems. Based on a review of relevant literature, we present and discuss an index of 13 such indicators, which, when identified in an agroecosystem, suggest that it is resilient and endowed with the capacity for adaptation and transformation. Absence of these indicators identifies points of intervention for managers and stakeholders to build resilience where there is vulnerability. The indicators encompass various phases in the adaptive cycle and seek to link core aspects of social-ecological systems. We stress the strong societal need for building resilience in agroecosystems and advocate for a broader way of evaluating resilience in agroecosystems. Copyright © 2012 by the author(s). Published here under license by the Resilience Alliance.


Kamstrup P.R.,Copenhagen University
Atherosclerosis | Year: 2010

The aim of this review is to summarize present evidence of a causal association of lipoprotein(a) with risk of ischemic heart disease (IHD). Evidence for causality includes reproducible associations of a proposed risk factor with risk of disease in epidemiological studies, evidence from in vitro and animal studies in support of pathophysiological effects of the risk factor, and preferably evidence from randomized clinical trials documenting reduced morbidity in response to interventions targeting the risk factor. Elevated and in particular extreme lipoprotein(a) levels have in prospective studies repeatedly been associated with increased risk of IHD, although results from early studies are inconsistent. Data from in vitro and animal studies implicate lipoprotein(a), consisting of a low density lipoprotein particle covalently bound to the plasminogen-like glycoprotein apolipoprotein(a), in both atherosclerosis and thrombosis, including accumulation of lipoprotein(a) in atherosclerotic plaques and attenuation of t-PA mediated plasminogen activation. No randomized clinical trial of the effect of lowering lipoprotein(a) levels on IHD prevention has ever been conducted. Lacking evidence from randomized clinical trials, genetic studies, such as Mendelian randomization studies, can also support claims of causality. Levels of lipoprotein(a) are primarily determined by variation in the LPA gene coding for the apolipoprotein(a) moiety of lipoprotein(a), and genetic epidemiologic studies have documented association of LPA copy number variants, influencing levels of lipoprotein(a), with risk of IHD. In conclusion, results from epidemiologic, in vitro, animal, and genetic epidemiologic studies support a causal association of lipoprotein(a) with risk of IHD, while results from randomized clinical trials are presently lacking. © 2010 Elsevier Ireland Ltd.


Buchmann K.,Copenhagen University
Journal of Fish Diseases | Year: 2012

Vertebrates mount a series of immune reactions when invaded by helminths but antihelmintic immune strategies allow, in many cases, the first invaders of the non-immune host to survive for prolonged periods, whereas subsequent larval invaders of the same parasite species face increased host resistance and thereby decreased colonization success. This concomitant immunity may represent a trade-off between adverse side effects (associated with killing of large helminths in the host tissue) and the need for future protection against invasion. Encapsulation and isolation of large live endoparasitic larvae may be associated with less pathology compared to coping with excess dead parasite tissue in host organs. Likewise, live adult nematodes may be accepted in tissues at a certain activity level for the same reasons. Various host cell receptors bind helminth molecules after which signal-transducing events lead to mobilization of specific reaction patterns depending on the combination of receptors and ligands involved. Both innate and adaptive responses (humoral and cellular) are prominent actors, but skewing of the Th1 lymphocyte response towards a Th2 type is a characteristic element of antihelminthic responses in mammalian hosts. Similar patterns may be expected also to occur in at least some fish species, such as salmonids, producing relevant cytokines, MHCII and CD4+ cells required for these lymphocyte subpopulations. Atlantic cod, Gadus morhua L., is without these immunological elements that indicate that alternative reaction pathways exist in at least some fish groups. Recent achievements within teleost immunology have made it possible to track these host responses in fish and the present work outlines the main immune reactions in fish against helminths and suggests three experimental fish models for exploration of these immune pathways in fish infected with nematodes. © 2012 Blackwell Publishing Ltd.


Gill D.J.,Institute of Molecular and Cell Biology IMCB | Clausen H.,Copenhagen University | Bard F.,Institute of Molecular and Cell Biology IMCB
Trends in Cell Biology | Year: 2011

O-GalNAc glycosylation of proteins confers essential structural, protective and signaling roles in eumetazoans. Addition of O-glycans onto proteins is an extremely complex process that regulates both sites of attachment and the types of oligosaccharides added. Twenty distinct polypeptide GalNAc-transferases (GalNAc-Ts) initiate O-glycosylation and fine-tuning their expression provides a mechanism for regulating this action. Recently, a new mode of regulation has emerged where activation of Src kinase selectively redistributes Golgi-localized GalNAc-Ts to the ER. This relocalization results in a strong increase in the density of O-glycan decoration. In this review, we discuss how different mechanisms can regulate the number and the types of O-glycans decorating proteins. In addition, we speculate how Src-dependent relocation of GalNAc-Ts could play an important role in cancerous cellular transformation. © 2010 Elsevier Ltd.


Thomsen H.S.,Copenhagen University
European Radiology | Year: 2011

This editorial reviews the way in which the facts related to the safety of iodinated and gadolinium based contrast agents have emerged over the last two decades. This is especially important given their ever increasing usage in modern computed tomographic (CT) and Magnetic resonance imaging (MRI) examinations. It also provides a very useful educational resume of this complex subject. © 2010 European Society of Radiology.


Simonsen P.E.,Copenhagen University | Mwakitalu M.E.,National Institute for Medical Research
Parasitology Research | Year: 2013

Lymphatic filariasis (LF) is a disabling and disfiguring disease resulting from a mosquito-borne parasitic infection. It is a major public health problem in many countries with a warm climate. Research and control activities have mainly focused on LF in rural areas where it also has its major impact. However, with rapid and unplanned growth of cities in the developing world, there is a need also to consider LF transmission and control in urban settings. Here, we review currently available knowledge on urban LF and the environmental and socio-economic basis for its occurrence. Among the three parasite species causing LF in humans, only Wuchereria bancrofti has been documented to have a significant potential for urban transmission. This is primarily because one of its vectors, Culex quinquefasciatus, thrives and proliferates excessively in crowded city areas with poor sanitary, sewerage and drainage facilities. For this reason, urban LF also often shows a marked focality in distribution, with most cases clustered in areas inhabited by the less privileged city populations. More knowledge on urban LF is needed, in particular on its socio-economic and human behavioural context, on the potential for transmission in regions where other LF vector species predominate, and on rapid methods for identification and mapping of risk areas, to provide a strong evidence base for its control. © 2012 The Author(s).


Jensen L.J.,Gronnegaardsvej | Holstein-Rathlou N.-H.,Copenhagen University
Journal of Cerebral Blood Flow and Metabolism | Year: 2013

Despite recent advances in our understanding of the molecular and cellular mechanisms behind vascular conducted responses (VCRs) in systemic arterioles, we still know very little about their potential physiological and pathophysiological role in brain penetrating arterioles controlling blood flow to the deeper areas of the brain. The scope of the present review is to present an overview of the conceptual, mechanistic, and physiological role of VCRs in resistance vessels, and to discuss in detail the recent advances in our knowledge of VCRs in brain arterioles controlling cerebral blood flow. We provide a schematic view of the ion channels and intercellular communication pathways necessary for conduction of an electrical and mechanical response in the arteriolar wall, and discuss the local signaling mechanisms and cellular pathway involved in the responses to different local stimuli and in different vascular beds. Physiological modulation of VCRs, which is a rather new finding in this field, is discussed in the light of changes in plasma membrane ion channel conductance as a function of health status or disease. Finally, we discuss the possible role of VCRs in cerebrovascular function and disease as well as suggest future directions for studying VCRs in the cerebral circulation. © 2013 ISCBFM All rights reserved.


Vallgarda S.,Copenhagen University
Health Policy | Year: 2012

Nudging, or libertarian paternalism, is presented as a new and ethically justified way of improving people's health. It has proved influential and is currently taken up by the governments in the US, the UK and France. One may question the claim that the approach is new, in any case it has many similarities with the idea of "making healthy choices easier" Whether the approach is better from an ethical perspective depends on the ethical principles one holds. From a paternalistic perspective there could be no objections, but from a libertarian, there are several. Contrary to what the authors state, libertarian paternalism is an oxymoron. © 2011 Elsevier Ireland Ltd.


At least 30% of patients with rheumatoid arthritis (RA) do not respond to biologic agents, which emphasizes the need of predictive biomarkers. We aimed to identify microRNAs (miRNAs) predictive of response to adalimumab in 180 treatment-naïve RA patients enrolled in the OPtimized treatment algorithm for patients with early RA (OPERA) Study, an investigator-initiated, prospective, double-blind placebo-controlled study. Patients were randomized to adalimumab 40 mg (n=89) or placebo–adalimumab (n=91) subcutaneously in combination with methotrexate. Expressions of 377 miRNAs were determined using TaqMan Human MicroRNA LDA, A Card v2.0 (Applied Biosystems). Associations between miRNAs and treatment response were tested using interaction analyses. MiRNAs with a P-value <0.05 using three different normalizations were included in a multivariate model. After backwards elimination, the combination of low expression of miR-22 and high expression of miR-886.3p was associated with EULAR good response. Future studies to assess the utility of these miRNAs as predictive biomarkers are needed.The Pharmacogenomics Journal advance online publication, 5 May 2015; doi:10.1038/tpj.2015.30. © 2015 Macmillan Publishers Limited


Jensen T.B.,Copenhagen University
Preventive veterinary medicine | Year: 2012

Mortality of sows is a major problem for pig production worldwide. In this study, we used hierarchical multivariable logistic analyses to investigate different risk factors for mortality at the sow and herd level in herds with group-housed pregnant sows. Data included 3652 pregnant and 1266 lactating sows from 34 sow herds. A clinical examination for 16 clinical signs was carried out for each sow, and information about 16 herd related factors was obtained by interviews. Farm records were used to obtain information about whether or not sows died suddenly or were euthanized within 3 months after the clinical examination. Factors increasing the risk of sow mortality in the gestation unit were solid pen floors (OR=1.87), presence of vulva bites (OR=1.73) and unwillingness to stand when approached (OR=1.62). Factors increasing the risk of sow mortality in the lactation unit were pale vulva color (OR=12.69), body leanness (OR=4.11), and presence of shoulder ulcers (OR=2.89). The estimated between herd variation was small. Thus, the findings for the sow level variables may be generally applicable for sows in herds with group housed systems. Copyright © 2011 Elsevier B.V. All rights reserved.


Erler J.T.,Copenhagen University | Linding R.,Technical University of Denmark
Cell | Year: 2012

Drug development for complex diseases is shifting from targeting individual proteins or genes to systems-based attacks targeting dynamic network states. Lee et al. now reveal how the progressive rewiring of a signaling network over time following EGF receptor inhibition leaves triple-negative breast tumors vulnerable to a second, later hit with DNA-damaging drugs, demonstrating that time- and order-dependent drug combinations can be more efficacious in killing cancer cells. © 2012 Elsevier Inc.


Stein R.F.,Michigan State University | Nordlund A.,Copenhagen University
Astrophysical Journal Letters | Year: 2012

Magnetoconvection can produce an active region without an initial coherent flux tube. A simulation was performed where a uniform, untwisted, horizontal magnetic field of 1kG strength was advected into the bottom of a computational domain 48 Mm wide by 20 Mm deep. The up and down convective motions produce a hierarchy of magnetic loops with a wide range of scales, with smaller loops riding "piggy-back" in a serpentine fashion on larger loops. When a large loop approaches the surface, it produces a small active region with a compact leading spot and more diffuse following spots. © 2012. The American Astronomical Society. All rights reserved..


Kristensen M.T.,Copenhagen University
European Journal of Physical and Rehabilitation Medicine | Year: 2011

Having a hip fracture is considered one of the most fatal fractures for elderly people, resulting in impaired function, and increased morbidity and mortality. This challenges clinicians in identifying patients at risk of worse outcome, in order to optimise and intensify treatment in these patients. A variety of factors such as age, prefracture function and health status, fracture type, pain, anaemia, muscle strength, and the early mobility level have been shown to influence patient outcome. Thus, the outcome of patients with hip fracture is considered multi-factorial, and can therefore not be related to just one or two single factors. The current article reviews important factors affecting the functional prognosis, and clinicians are encouraged to include all factors potentially influencing the outcome of patients with hip fracture in their individualised treatment and rehabilitation plan. Especially, older age and having a low prefracture functional level are considered strong factors.


Groes-Green C.,Copenhagen University
Medical Anthropology: Cross Cultural Studies in Health and Illness | Year: 2012

Participation in young peoples' sexual cultures in Maputo, Mozambique led to reflections about the field dynamics of power, participation, desire, and discomfort. Structural inequalities of race, gender, and educational status resulted in informants seeing me as a morally righteous person to whom they could not give open accounts about sexual practice. Attempting to overcome these barriers, I participated in excessive nightlife activities, and as a consequence they began viewing me as a more accepting and reliable person. Although breaking down these barriers provided invaluable insight into their sexual culture, it also caused anxiety and troubling desires vis-à-vis informants. I discuss how anthropologists, through fieldwork are transformed from powerful seducers of informants to objects of informants' seduction. This creates dilemmas for the anthropologist whose fieldwork depends on informants' continued participation. I show how negotiating the risks of participation may simultaneously satisfy the desire for knowledge and curb erotic desires. © 2012 Copyright Taylor and Francis Group, LLC.


Zafar T.,Aix - Marseille University | Watson D.,Copenhagen University
Astronomy and Astrophysics | Year: 2013

Among the key parameters defining the interstellar media (ISM) of galaxies is the fraction of the metals that are locked up in dust: the metals-to-dust ratio. This ratio bears not only on the ISM and its evolution, but also particularly on the origin of cosmic dust. We combine extinction and abundance data from γ-ray burst (GRB) afterglows with similar data from quasar (QSO) foreground absorbers, as well as from multiply-imaged galaxy-lensed QSOs, to determine the metals-to-dust ratios for lines of sight through a wide diversity of galaxies from blue, dwarf starbursts to massive ellipticals, across a vast range of redshifts z = 0.1-6.3, and nearly three orders of magnitude of column density and metal abundance. The GRB and lensed QSO extinction methods are the most reliable that are available outside the Local Group (LG), allowing absolute extinction measurements. We thus determine the metals-to-dust ratio in a unique way, providing direct determinations of in situ gas and dust columns without recourse to assumptions with large uncertainties. We find that the metals-to-dust ratios in these systems are surprisingly close to the value for the LG, with a mean value of 1021.2 cm-2 AV mag-1 and a standard deviation of 0.3 dex, compared to the Galactic value of 1021.3 cm-2AV mag-1 (in units of the Galactic gas-to-dust ratio). There is no evidence of deviation from this mean ratio as a function of metallicity, even down to our lowest metallicity of 0.01 Z/Z⊙. The lack of any obvious dependence of the metals-to-dust ratio on column density, galaxy type or age, redshift, or metallicity indicates a close correspondence between the formation of the metals and the formation of dust. Any delay between the formation of metals and dust must be shorter than the typical metal-enrichment times of these galaxies, i.e. shorter than a few Myr. Formation of the bulk of the dust in low mass stars is therefore ruled out by these data at any cosmic epoch. Furthermore, dust destruction must not dominate over formation/growth in virtually any galaxy environment. The close correlation between metals and dust is a natural consequence of the formation of the bulk of cosmic dust in supernovae. Grain growth in the ISM, if it is to be the dominant cosmic dust formation mechanism, is strongly constrained by these data to operate on very short timescales. © ESO, 2013.


Alsmith A.J.T.,Copenhagen University | Longo M.R.,University of London
Consciousness and Cognition | Year: 2014

I am clearly located where my body is located. But is there one particular place inside my body where I am? Recent results have provided apparently contradictory findings about this question. Here, we addressed this issue using a more direct approach than has been used in previous studies. Using a simple pointing task, we asked participants to point directly at themselves, either by manual manipulation of the pointer whilst blindfolded or by visually discerning when the pointer was in the correct position. Self-location judgements in haptic and visual modalities were highly similar, and were clearly modulated by the starting location of the pointer. Participants most frequently chose to point to one of two likely regions, the upper face or the upper torso, according to which they reached first. These results suggest that while the experienced self is not spread out homogeneously across the entire body, nor is it localised in any single point. Rather, two distinct regions, the upper face and upper torso, appear to be judged as where "I" am. © 2013 Elsevier Inc.


Joyner M.J.,Mayo Medical School | Pedersen B.K.,Copenhagen University
Journal of Physiology | Year: 2011

In this paper we raise 'ten questions' broadly related to 'omics', the term systems biology, and why the new biology has failed to deliver major therapeutic advances for many common diseases, especially diabetes and cardiovascular disease. We argue that a fundamentally narrow and reductionist perspective about the contribution of genes and genetic variants to disease is a key reason 'omics' has failed to deliver the anticipated breakthroughs. We then point out the critical utility of key concepts from physiology like homeostasis, regulated systems and redundancy as major intellectual tools to understand how whole animals adapt to the real world. We argue that a lack of fluency in these concepts is a major stumbling block for what has been narrowly defined as 'systems biology' by some of its leading advocates. We also point out that it is a failure of regulation at multiple levels that causes many common diseases. Finally, we attempt to integrate our critique of reductionism into a broader social framework about so-called translational research in specific and the root causes of common diseases in general. Throughout we offer ideas and suggestions that might be incorporated into the current biomedical environment to advance the understanding of disease through the perspective of physiology in conjunction with epidemiology as opposed to bottom-up reductionism alone. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.


Sneppen K.,Copenhagen University | Dodd I.B.,University of Adelaide
PLoS Computational Biology | Year: 2012

Nucleosomes can be covalently modified by addition of various chemical groups on several of their exposed histone amino acids. These modifications are added and removed by enzymes (writers) and can be recognized by nucleosome-binding proteins (readers). Linking a reader domain and a writer domain that recognize and create the same modification state should allow nucleosomes in a particular modification state to recruit enzymes that create that modification state on nearby nucleosomes. This positive feedback has the potential to provide the alternative stable and heritable states required for epigenetic memory. However, analysis of simple histone codes involving interconversions between only two or three types of modified nucleosomes has revealed only a few circuit designs that allow heritable bistability. Here we show by computer simulations that a histone code involving alternative modifications at two histone positions, producing four modification states, combined with reader-writer proteins able to distinguish these states, allows for hundreds of different circuits capable of heritable bistability. These expanded possibilities result from multiple ways of generating two-step cooperativity in the positive feedback - through alternative pathways and an additional, novel cooperativity motif. Our analysis reveals other properties of such epigenetic circuits. They are most robust when the dominant nucleosome types are different at both modification positions and are not the type inserted after DNA replication. The dominant nucleosome types often recruit enzymes that create their own type or destroy the opposing type, but never catalyze their own destruction. The circuits appear to be evolutionary accessible; most circuits can be changed stepwise into almost any other circuit without losing heritable bistability. Thus, our analysis indicates that systems that utilize an expanded histone code have huge potential for generating stable and heritable nucleosome modification states and identifies the critical features of such systems. © 2012 Sneppen, Dodd.


Lund J.F.,Copenhagen University
Biodiversity and Conservation | Year: 2014

The literature on locally-based monitoring in the context of conservation of ecosystems and natural resources in developing countries displays a great deal of optimism about its prospects as a low-cost approach to gather information about conservation outcomes. Yet, this optimism stands in stark contrast to studies on co-management between States and local communities showing that such processes-in which communities and the State ostensibly work hand in hand on the monitoring and management of natural resources-are fraught with power struggles within communities as well as between communities and the State and that the information produced and communicated is often invoked in such struggles. Information produced and communicated in systems of locally-based monitoring will reflect these struggles in particular if such systems are bound up with processes of co-management or REDD+ in which the information can be perceived by those who monitor to be linked to claims over resource rights and associated benefits. In such situations, trust in locally-based monitoring should be tempered by scepticism and systems of checks and balances. © 2013 Springer Science+Business Media Dordrecht.


Korreman S.S.,Roskilde University | Korreman S.S.,Copenhagen University
Physics in Medicine and Biology | Year: 2012

This review considers the management of motion in photon radiation therapy. An overview is given of magnitudes and variability of motion of various structures and organs, and how the motion affects images by producing artifacts and blurring. Imaging of motion is described, including 4DCT and 4DPET. Techniques for monitoring motion in real time by use of surrogates are reviewed. Treatment planning for various motion-management treatment delivery strategies is discussed, including choice of planning image, treatment field margins and dose calculation. Imaging techniques displaying motion in the treatment room for pre-treatment as well as real-time imaging for localization and verification are covered, and their use for various motion-management treatment delivery techniques is discussed. Use of motion management for different treatment sites - breast, lung and other sites - is elaborated, and gating, breath-hold and beam tracking strategies are described. Suggestions are given for breast and lung for practicable protocols for routine clinical use of motion management, including decision strategies. Finally, a perspective of the future of motion management in photon radiation therapy is given. © 2012 Institute of Physics and Engineering in Medicine.


Gastrin and cholecystokinin (CCK) are homologous hormone systems known to regulate gastric acid secretion, gallbladder emptying, and cell growth in the pancreas and stomach. They are, however, also involved in the development and secretory functions of pancreatic islet cells. For instance, foetal and neonatal islets express significant amounts of gastrin, and human as well as porcine islet cells express the gastrin/CCK-B receptor abundantly. Therefore, exogenous gastrin and CCK peptides stimulate insulin and glucagon secretion in man. Accordingly, endogenous hypergastrinaemia is accompanied by islet cell hyperplasia and increased insulin secretion. Conventionally, the effect of gastrointestinal hormones on insulin secretion (the incretin effect) has been defined and quantified in relation to oral versus intravenous glucose loadings. Under these unphysiological conditions, the release of gastrin and CCK and, hence, their effect on insulin secretion are modest in comparison with the effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1). Consequently, the interest of CCK and gastrin in incretin research has for decades been limited. A few years ago, however, it was suggested that gastrin together with epidermal growth factor or later GLP-1 might stimulate beta cell growth and secretion. Recent studies have shown that the combination of gastrin and GLP-1 actually restores normoglycaemia in diabetic mice. Therefore, a short review of the incretin system in a broader functional context that includes gastrin and CCK peptides may be timely. © 2011 The Author. Acta Physiologica © 2011 Scandinavian Physiological Society.


This mini review outlines studies of cell volume regulation in two closely related mammalian cell lines: nonadherent Ehrlich ascites tumour cells (EATC) and adherent Ehrlich Lettre ascites (ELA) cells. Focus is on the regulatory volume decrease (RVD) that occurs after cell swelling, the volume regulatory ion channels involved, and the mechanisms (cellular signalling pathways) that regulate these channels. Finally, I shall also briefly review current investigations in these two cell lines that focuses on how changes in cell volume can regulate cell functions such as cell migration, proliferation, and programmed cell death. Copyright © 2011 S. Karger AG, Basel.


Rukov J.L.,Tel Aviv University | Rukov J.L.,Copenhagen University | Shomron N.,Tel Aviv University
Trends in Molecular Medicine | Year: 2011

The field of pharmacogenomics aims to predict which drugs will be most effective and safe for a particular individual based on their genome sequence or expression profile, thereby allowing personalized treatment. The bulk of pharmacogenomic research has focused on the role of single nucleotide polymorphisms, copy number variations or differences in gene expression levels of drug metabolizing or transporting genes and drug targets. In this review paper, we focus instead on microRNAs (miRNAs): small noncoding RNAs, prevalent in metazoans, that negatively regulate gene expression in many cellular processes. We discuss how miRNAs, by regulating the expression of pharmacogenomic-related genes, can play a pivotal role in drug efficacy and toxicity and have potential clinical implications for personalized medicine. © 2011 Elsevier Ltd.


Ryan R.P.,University College Cork | Tolker-Nielsen T.,Copenhagen University | Dow J.M.,University College Cork
Trends in Microbiology | Year: 2012

The second messenger cyclic di-GMP has emerged as a central regulator of many important bacterial processes including biofilm formation and virulence. Although the pathways of cyclic di-GMP synthesis and degradation have been established, the mechanisms by which this second messenger exerts its action on diverse cellular functions remain relatively poorly understood. Recent studies report considerable advances in identifying different classes of cyclic di-GMP effectors; these include the PilZ protein domain, transcription factors, proteins involved in RNA processing and riboswitches. Here, we review this range of cyclic di-GMP effectors and the biological processes that they govern using examples from several different bacteria. © 2012 Elsevier Ltd.


Lalueza-Fox C.,Institute of Evolutionary Biology CSIC UPF | Gilbert M.T.P.,Copenhagen University
Current Biology | Year: 2011

In order to understand the genetic basis for the evolutionary success of modern humans, it is necessary to compare their genetic makeup to that of closely related species. Unfortunately, our closest living relatives, the chimpanzees, are evolutionarily quite distant. With the advent of ancient DNA study and more recently paleogenomics - the study of the genomes of ancient organisms - it has become possible to compare human genomes to those of much more closely related groups. Our closest known relatives are the Neanderthals, which evolved and lived in Europe and Western Asia, from about 600,000 years ago until their disappearance around 30,000 years ago following the expansion of anatomically modern humans into their range. The closely related Denisovans are only known by virtue of their DNA, which has been extracted from bone fragments dating around 30,000 to 50,000 years ago found in a single Siberian cave. Analyses of Neanderthal and Denisovan nuclear and mitochondrial genomes have revealed surprising insights into these archaic humans as well as our own species. The genomes provide a preliminary catalogue of derived amino acids that are specific to all extant modern humans, thus offering insights into the functional differences between the three lineages. In addition, the genomes provide evidence of gene flow between the three lineages after anatomically modern humans left Africa, drastically changing our view of human evolution. © 2011 Elsevier Ltd.


Aspberg A.,Copenhagen University
Journal of Histochemistry and Cytochemistry | Year: 2012

The aggregating proteoglycans of the lectican family are important components of extracellular matrices. Aggrecan is the most well studied of these and is central to cartilage biomechanical properties and skeletal development. Key to its biological function is the fixed charge of the many glycosaminoglycan chains, that provide the basis for the viscoelastic properties necessary for load distribution over the articular surface. This review is focused on the globular domains of aggrecan and their role in anchoring the proteoglycans to other extracellular matrix components. The N-terminal G1 domain is vital in that it binds the proteoglycan to hyaluronan in ternary complex with link protein, retaining the proteoglycan in the tissue. The importance of the C-terminal G3 domain interactions has recently been emphasized by two different human hereditary disorders: autosomal recessive aggrecan-type spondyloepimetaphyseal dysplasia and autosomal dominant familial osteochondritis dissecans. In these two conditions, different missense mutations in the aggrecan C-type lectin repeat have been described. The resulting amino acid replacements affect the ligand interactions of the G3 domain, albeit with widely different phenotypic outcomes. © The Author(s) 2012.


Hutchings M.,Copenhagen University
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Positron emission tomography/computed tomography (PET/CT) has emerged as the most accurate tool for staging, treatment monitoring, and response evaluation in Hodgkin lymphoma (HL). Accurate staging and restaging are very important for the optimal management of HL, but we are only beginning to understand how to use PET/CT to improve treatment outcome. More precise determination of disease extent may result in more precise pretreatment risk stratification, and is also essential for the minimal and highly individualized radiotherapy volumes of the present era. Several trials are currently investigating the use of PET/CT for early response-adapted therapy, with therapeutic stratification based on interim PET/CT results. Posttreatment PET/CT is a cornerstone of the revised response criteria and enables the selection of advanced-stage patients without the need for consolidation radiotherapy. Once remission is achieved after first-line therapy, PET/CT seems to have little or no role in the routine surveillance of HL patients. PET/CT looks promising for the selection of therapy in relapsed and refractory disease, but its role in this setting is still unclear.


The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms, in which a stem cell lesion induces an autonomous proliferative advantage. In addition to the JAK2V617 mutation several other mutations have been described. Recently chronic inflammation has been proposed as a trigger and driver of clonal evolution in MPNs. Herein, it is hypothesized that sustained inflammation may elicit the stem cell insult by inducing a state of chronic oxidative stress with elevated levels of reactive oxygen species (ROS) in the bone marrow, thereby creating a high-risk microenvironment for induction of mutations due to the persistent inflammation-induced oxidative damage to DNA in hematopoietic cells. Alterations in the epigenome induced by the chronic inflammatory drive may likely elicit a "epigenetic switch" promoting persistent inflammation. The perspectives of chronic inflammation as the driver of mutagenesis in MPNs are discussed, including early intervention with interferon-alpha2 and potent anti-inflammatory agents (e.g. JAK1-2 inhibitors, histone deacetylase inhibitors, DNA-hypomethylators and statins) to disrupt the self-perpetuating chronic inflammation state and accordingly eliminating a potential trigger of clonal evolution and disease progression with myelofibrotic and leukemic transformation. © 2012 Elsevier Ltd.


Krustrup P.,Copenhagen University
Scandinavian journal of medicine & science in sports | Year: 2010

The present special issue of Scandinavian Journal of Medicine & Science in Sports deals with health and fitness benefits of regular participation in small-sided football games. One review article and 13 original articles were the result of a 2-year multi-center study in Copenhagen and Zurich and include studies of different age groups analyzed from a physiological, medical, social and psychological perspective. The main groups investigated were middle-aged, former untrained, healthy men and women who were followed for up to 16 months. In addition, elderly, children and hypertensive patients were studied. A summary and interpretations of the main findings divided into an analysis of the physical demands during training of various groups and the effect of a period of training on performance, muscle adaptations and health profile follow. In addition, social and psychological effects on participation in recreational football are considered, the comparison of football training and endurance running is summarized and the effects of football practice on the elderly and children and youngsters are presented.


Scheike T.H.,Copenhagen University | Zhang M.-J.,Medical College of Wisconsin
Journal of Statistical Software | Year: 2011

In this paper we describe flexible competing risks regression models using the comp.risk() function available in the timereg package for R based on Scheike et al. (2008). Regression models are specified for the transition probabilities, that is the cumulative incidence in the competing risks setting. The model contains the Fine and Gray (1999) model as a special case. This can be used to do goodness-of-fit test for the subdistribution hazards' proportionality assumption (Scheike and Zhang 2008). The program can also construct confidence bands for predicted cumulative incidence curves. We apply the methods to data on follicular cell lymphoma from Pintilie (2007), where the competing risks are disease relapse and death without relapse. There is important non-proportionality present in the data, and it is demonstrated how one can analyze these data using the flexible regression models.


Nielsen S.S.,Copenhagen University
Preventive Veterinary Medicine | Year: 2011

The Danish dairy industry initiated a voluntary, producer-paid control programme on Mycobacterium avium subsp. paratuberculosis (MAP) in 2006. Approximately 28% of the dairy herds, including 40% of the cows, are part of the programme. Farmers' reasons for participation are of great importance for the success of voluntary disease control programmes. This study was carried out to determine these reasons. Questionnaires with seven close-ended questions were mailed to the 1177 voluntary participants in 2008. A total of 1013 (86%) responded, and multiple reasons could be given by each farmer. The distribution of reasons for participation in the programme was: (1) control to increase animal health (91%); (2) certification "free of MAP infection" within 4-10 years (87%); (3) control to avoid production losses associated with MAP infections (86%); (4) control of MAP infections to increase consumer safety (64%); (5) certification for sale of livestock (58%); (6) control following production losses (48%); and (7) certification "free of MAP infection" within 1-3 years (31%).It was not possible to rank the reasons for participation since weighting of responses was not included. Therefore, the relative importance of the reasons given could not be determined. Based on the farmers' responses, control of MAP infections to increase animal health and avoid production losses were frequent reasons for participating in the Danish paratuberculosis control programme. The results also indicate that implementation of a certification programme would be desired by farmers. Animal health advisors should consider the diversity of participation reasons and address the specific reasons of individual farmers when establishing a strategy for control of MAP infections in a herd. © 2010 Elsevier B.V.


Hou J.,Copenhagen University
Neurobiology of aging | Year: 2012

The present study is aimed to assess age-related structural changes in corpus callosum with stereology in 21 postmortem human brains without neuropathology, of age 65-75 (Group A, n = 7), 80-85 (Group B, n = 7), and 94-105 (Group C, n = 7) years. Cross-sectional area, fiber number and density decrease in Group B compared with Group A, then remain unchanged in Group C. Mean fiber diameter increases with age. Cross-sectional area shows strong positive correlation to fiber numbers and negative correlation to mean fiber thickness. With age, modest but significant change in fiber size including a decrease in the percentage of 1-2-μm fibers and an increase in 2-3-μm fibers was observed. Fiber density shows a steeper decline with age in the anterior compared with posterior segments. Neurodegeneration is an ongoing process where the anterior corpus callosum is more susceptible to age-related degeneration. Corpus callosum cross-sectional area atrophy is mostly related to decline in fiber number and density rather than demyelination, with preferential disruption of small caliber fibers. Copyright © 2012 Elsevier Inc. All rights reserved.


Pinborg A.,Copenhagen University
Seminars in Reproductive Medicine | Year: 2012

Worldwide freezing and thawing of embryos has been increasingly used since the first infant was born as a result of this technique in 1984. The use of frozen embryo replacement (FER) currently even exceeds the number of fresh cycles performed in some countries. This article discusses the pros and cons of FER versus fresh-embryo transfer with regard to both single-cycle and cumulative pregnancy and delivery rates. The review discusses the obvious advantages of FER: minimizing the proportion of pharmacological and surgical treatments, and lowering the risk of ovarian hyperstimulation syndrome and multiple pregnancies, thereby increasing the safety for mother and child. Finally the article describes the accumulating literature on perinatal and long-term child outcome after transfer of frozen/thawed embryos, including a discussion on the concerns regarding cryo techniques and their possible roles in the subsequent development of fetus and child. Because larger and more detailed data sets are available for early cleavage-stage embryo freezing and slow freezing, they are the main focus of this review. Copyright © 2012 by Thieme Medical Publishers, Inc.


Thyssen J.P.,Copenhagen University | Kezic S.,Coronel Institute of Occupational Health
Journal of Allergy and Clinical Immunology | Year: 2014

The epidermis protects human subjects from exogenous stressors and helps to maintain internal fluid and electrolyte homeostasis. Filaggrin is a crucial epidermal protein that is important for the formation of the corneocyte, as well as the generation of its intracellular metabolites, which contribute to stratum corneum hydration and pH. The levels of filaggrin and its degradation products are influenced not only by the filaggrin genotype but also by inflammation and exogenous stressors. Pertinently, filaggrin deficiency is observed in patients with atopic dermatitis regardless of filaggrin mutation status, suggesting that the absence of filaggrin is a key factor in the pathogenesis of this skin condition. In this article we review the various causes of low filaggrin levels, centralizing the functional and morphologic role of a deficiency in filaggrin, its metabolites, or both in the etiopathogenesis of atopic dermatitis. © 2014 American Academy of Allergy, Asthma and Immunology.


INTRODUCTION: A combination of carboplatin and paclitaxel is often used as first line chemotherapy for treatment of ovarian cancer. Therefore the use of imaging biomarkers early after initiation of treatment to determine treatment sensitivity would be valuable in order to identify responders from non-responders. In this study we describe the non-invasive PET imaging of glucose uptake and cell proliferation using 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) for early assessment of treatment response in a pre-clinical mouse model of human ovarian cancer treated with carboplatin and paclitaxel.METHODS: In vivo uptake of FLT and FDG in human ovarian cancer xenografts in mice (A2780) was determined before treatment with carboplatin and paclitaxel (CaP) and repeated day 1, 4 and 8 after treatment start. Tracer uptake was quantified using small animal PET/CT. Tracer uptake was compared with gene expression of Ki67, TK1, GLUT1, HK1 and HK2.RESULTS: Tumors in the CaP group was significantly smaller than in the control group (p=0.03) on day 8. On day 4 FDG SUVmax ratio was significantly lower in the CaP group compared to the control group (105 ± 4% vs 138 ± 9%; p=0.002) and on day 8 the FDG SUVmax ratio was lower in the CaP compared to the control group (125 ± 13% vs 167 ± 13%; p=0.05). On day 1 the uptake of FLT SUVmax ratio was 89 ± 9% in the CaP group and 109 ± 6% in the control group; however the difference was not statistically significant (p=0.08).CONCLUSIONS: Our data suggest that both FDG and FLT PET may be used for the assessment of anti-tumor effects of a combination of carboplatin and paclitaxel in the treatment of ovarian cancer. FLT provides an early and transient signal and FDG a later and more prolonged response. This underscores the importance of optimal timing between treatment and FLT or FDG imaging since treatment response may otherwise be overlooked.


Lidegaard O.,Copenhagen University
Expert Opinion on Drug Safety | Year: 2014

Introduction: This paper reviews the risk of thrombosis with use of different types of hormonal contraception in women of different ages.Areas covered: Combined hormonal contraceptives with desogestrel, gestodene, drospirenone or cyproterone acetate (high-risk products) confer a sixfold increased risk of venous thromboembolism as compared with nonusers, and about twice the risk as compared with users of products with norethisterone, levonorgestrel or norgestimate (low-risk products). Transdermal patches and vaginal ring belong to high-risk products. The risk of thrombotic stroke and myocardial infarction is increased 50-100% with use of combined products, with little difference in risk between different progestins. Progestin-only products do not confer any increased risk of venous or arterial thrombosis, except for progestin depot, which may double the risk of venous thrombosis.Expert opinion: First choice in women below 35 years should be a combined low-risk pill, that is, with a second-generation progestin, with the lowest compliable dose of estrogen. Young women with risk factors of thrombosis such as age above 35 years, genetic predispositions, adiposity, polycystic ovary syndrome, diabetes, smoking, hypertension or migraine with aura should not use high-risk products, but should primarily consider progestin-only products, and be careful to use low-risk combined products. © 2014 Informa UK, Ltd.


Nielsen O.H.,Copenhagen University | Loftus E.V.,Mayo Medical School | Jess T.,Statens Serum Institute
BMC Medicine | Year: 2013

Background: Tumor necrosis factor (TNF)-α inhibitors are increasingly being used in inflammatory bowel disease (IBD). Because this chronic intestinal disorder often affects women of fertile age, it is essential to assess the effect of biologics on pregnancy outcome.Methods: We performed a systematic review of the English-language literature to investigate if treatment with TNF-α blockers during pregnancy in women with IBD increases the risk of spontaneous abortions, preterm delivery, stillbirth, low birth weight, congenital malformations, or risk of infections in the offspring. Of 552 articles and abstracts reviewed, 58 articles or abstracts with unique content were identified and included in this systematic review. However, most presentations were case reports or case series supplied by a limited number of observational studies. No randomized controlled studies were available.Results: TNF-α inhibitors do not seem to affect either outcome of pregnancy in mothers with IBD, or the outcome in the offspring (congenital malformations and immunosuppression). Further, recent data have not identified any increased risk of infections in the first year of life in the offspring of mothers who received biologics, even in combination with immunomodulators (thiopurines).Conclusions: From the present systematic review, no association was found between administration of TNF inhibitors for IBD during pregnancy and adverse pregnancy outcome or congenital abnormalities. Further, no increased relative risk of infections has been reported in the first year of life in offspring of mothers who received biologics. Biologics should be discontinued during pregnancy solely if the IBD is in remission using the same stopping criteria as for patients with IBD in general, as uncontrolled activity of IBD may expose the mother and child to a risk greater than those only potentially coming from the use of TNF-α inhibitors. In such cases, inoculation of the offspring with live vaccines is contraindicated until the biologic agent is no longer detectable in the child's circulation. © 2013 Nielsen et al.; licensee BioMed Central Ltd.


Bolwig T.G.,Copenhagen University
Journal of ECT | Year: 2014

BACKGROUND: Since the 1970s, a number of neuroimaging studies of electroconvulsive therapy (ECT) have been conducted to elucidate the working action of this highly efficacious treatment modality. The technologies used are single photon emission tomography, positron emission tomography, magnetic resonance imaging, magnetic resonance spectroscopy, and quantitative electroencephalography. METHODS: A PubMed literature search with focus on clinical studies was made from the inception of the database until December 2013 using the search terms electroconvulsive therapy and neuroimaging. RESULTS: Early methods allowing only identification of global changes of cerebral blood flow and cerebral metabolism show considerable ictal increases of these measures, which normalize during the postictal period. Later methodological developments have given access to measurements of minute activity changes in localized cortical and subcortical areas of the brain and have revealed differences in neurophysiology and metabolism between the hyperactive ictal state and the restorative interictal/postictal periods. Recent magnetic resonance imaging studies seem to pave way for new insights into ECT's effects on increased connectivity in the brain during depression. CONCLUSION: The existing data reveal considerable variations among studies and therefore do not yet allow the formulation of a unified hypothesis for the mechanism of ECT. The rapid developments in imaging technology, however, hold promises for further elucidation of the mode of action of ECT. Copyright © 2014 by Lippincott Williams & Wilkins.


Biomembranes are thin capacitors with the unique feature of displaying phase transitions in a physiologically relevant regime. We investigate the voltage and lateral pressure dependence of their capacitance close to their chain melting transition. Because the gel and the fluid membrane have different area and thickness, the capacitance of the two membrane phases is different. In the presence of external fields, charges exert forces that can influence the state of the membrane, thereby influencing the transition temperature. This phenomenon is called "electrostriction". We show that this effect allows us to introduce a capacitive susceptibility that assumes a maximum in the melting transition with an associated excess charge. As a consequence, voltage regimes exist in which a small change in voltage can lead to a large uptake of charge and a large capacitive current. Furthermore, we consider electromechanical behavior such as pressure-induced changes in capacitance, and the application of such concepts in biology. © 2012 Biophysical Society.


Bangsbo J.,Copenhagen University
Scandinavian Journal of Medicine and Science in Sports | Year: 2015

Performance in most sports is determined by the athlete's technical, tactical, physiological and psychological/social characteristics. In the present article, the physical aspect will be evaluated with a focus on what limits performance, and how training can be conducted to improve performance. Specifically how intensified training, i.e., increasing the amount of aerobic high-intensity and speed endurance training, affects physiological adaptations and performance of trained subjects. Periods of speed endurance training do improve performance in events lasting 30 s-4 min, and when combined with aerobic high-intensity sessions, also performance during longer events. Athletes in team sports involving intense exercise actions and endurance aspects, such as soccer and basketball, can also benefit from intensified training. Speed endurance training does reduce energy expenditure and increase expression of muscle Na+, K+ pump α subunits, which may preserve muscle cell excitability and delay fatigue development during intense exercise. When various types of training are conducted in the same period (concurrent training), as done in a number of sports, one type of training may blunt the effect of other types of training. It is not, however, clear how various training modalities are affecting each other, and this issue should be addressed in future studies. © 2015 John Wiley & Sons A/S.


With the discovery of the central pathogenic role of tumor necrosis factor (TNF)-α in many immunoinflammatory diseases, specific inhibition of this pleiotropic cytokine has revolutionized the treatment of patients with several non-infectious inflammatory disorders. As a result, genetically engineered anti-TNF-α antibody constructs now constitute one of the heaviest medicinal expenditures in many countries. All currently used TNF antagonists may dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favorably, and safety can be severely impaired by immunogenicity, i.e., the ability of a drug to induce anti-drug antibodies (ADA). Assessment of ADA is therefore an important component of the evaluation of drug safety in both pre-clinical and clinical studies and in the process of developing less immunogenic and safer biopharmaceuticals. Therapeutics diagnostics, also called theranostics, i.e., monitoring functional drug levels and neutralizing ADA in the circulation, is central to more effective use of biopharmaceuticals. Hence, testing-based strategies rather than empirical dose-escalation may provide more cost-effective use of TNF antagonists as this allows therapies tailored according to individual requirements rather than the current universal approach to diagnosis. The objective of the present review is to discuss the reasons for recommending theranostics to implement an individualized use of TNF antagonists and to highlight some of the methodological obstacles that have obscured cost-effective ways of using these therapies. © Discovery Medicine.


Bugge M.,Copenhagen University
American Journal of Medical Genetics, Part A | Year: 2012

Body stalk anomaly is a severe defect of the abdominal wall with uncovered thoracic and/or abdominal organs. The umbilical cord is absent or very short. Here I present epidemiological and clinical data on 16 infants with body stalk anomaly. The 16 infants represent 3.4% of the 469 infants ascertained in an almost complete nationwide data set of live- and stillborn infants born with abdominal wall defects during the two decades 1970-1989 in Denmark. The prevalence was 0.12 per 10,000 live- and stillborn. Nine of the infants were stillbirths, seven were live births, and they all died shortly after birth. The gestational age at birth varied from 33 to 40 weeks. There was an excess of males M/F ratio: 2.2 (CI: 0.85-10.71). All infants had severe associated malformations. Among the most severe were: severe limb reduction defects (56%), absence of one kidney associated with malformations of genitalia and/or urinary bladder (62%), scoliosis (82%), and anal atresia (57%). A normal karyotype was found in all eight of the infants who were tested. There were two sets of twins; one discordant and one concordant. Mean maternal and paternal ages were 28.5 and 29.5 years, respectively, not significantly different from the mean parental ages of the Danish population during the same period. © 2012 Wiley Periodicals, Inc.


Nolan C.J.,Australian National University | Damm P.,Copenhagen University | Prentki M.,University of Montreal
The Lancet | Year: 2011

Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing β cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the β cells, and lessening of adipose tissue defects should be treatment priorities. © 2011 Elsevier Ltd.


Fisher P.M.,Copenhagen University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

A corticolimbic circuit including the amygdala and medial prefrontal cortex (mPFC) plays an important role in regulating sensitivity to threat, which is heightened in mood and anxiety disorders. Serotonin is a potent neuromodulator of this circuit; however, specific serotonergic mechanisms mediating these effects are not fully understood. Recent studies have evaluated molecular mechanisms mediating the effects of serotonin signalling on corticolimbic circuit function using a multi-modal neuroimaging strategy incorporating positron emission tomography and blood oxygen level-dependent functional magnetic resonance imaging. This multi-modal neuroimaging strategy can be integrated with additional techniques including imaging genetics and pharmacological challenge paradigms to more clearly understand how serotonin signalling modulates neural pathways underlying sensitivity to threat. Integrating these methodological approaches offers novel opportunities to identify mechanisms through which serotonin signalling contributes to differences in brain function and behaviour, which in turn can illuminate factors that confer risk for illness and inform the development of more effective treatment strategies.


Nielsen M.E.,University of Tubingen | Thordal-Christensen H.,Copenhagen University
Trends in Plant Science | Year: 2013

Penetration resistance is a well-described plant defense process, in which SOLUBLE N-ETHYLMALEIMIDE-SENSITIVE-FACTOR ATTACHMENT RECEPTOR (SNARE) proteins have essential roles in membrane fusion processes. Strong focal accumulation of these proteins at the site of attack by powdery mildew fungi has been considered important for their function. However, recent insight indicates that transcytosis, leading to the formation of exosomes, has an important role in this defense and, furthermore, that strong accumulation of these SNARE proteins with the exosomes is biologically irrelevant. These findings alter the established function of SNAREs in penetration resistance; therefore, in this opinion, we propose that PEN1 and its SNARE partners function on an endosome in their control of penetration resistance. © 2013 Elsevier Ltd.


Creixell P.,Technical University of Denmark | Schoof E.M.,Technical University of Denmark | Erler J.T.,Copenhagen University | Linding R.,Technical University of Denmark
Nature Biotechnology | Year: 2012

Cells employ highly dynamic signaling networks to drive biological decision processes. Perturbations to these signaling networks may attract cells to new malignant signaling and phenotypic states, termed cancer network attractors, that result in cancer development. As different cancer cells reach these malignant states by accumulating different molecular alterations, uncovering these mechanisms represents a grand challenge in cancer biology. Addressing this challenge will require new systems-based strategies that capture the intrinsic properties of cancer signaling networks and provide deeper understanding of the processes by which genetic lesions perturb these networks and lead to disease phenotypes. Network biology will help circumvent fundamental obstacles in cancer treatment, such as drug resistance and metastasis, empowering personalized and tumor-specific cancer therapies. © 2012 Nature America, Inc. All rights reserved.


Wulff-Nilsen C.,Copenhagen University
Proceedings of the Annual ACM-SIAM Symposium on Discrete Algorithms | Year: 2013

We give new deterministic bounds for fully-dynamic graph connectivity. Our data structure supports updates (edge insertions/deletions) in O(log 2n/ log log n) amortized time and connectivity queries in O(log n/ log log n) worst-case time, where n is the number of vertices of the graph. This improves the deterministic data structures of Holm, de Lichtenberg, and Thorup (STOC 1998, J.ACM 2001) and Thorup (STOC 2000) which both have O(log2 n) amortized update time and O(log n/ log log n) worst-case query time. Our model of computation is the same as that of Thorup, i.e., a pointer machine with standard AC0 instructions. Copyright © SIAM.


Wulff-Nilsen C.,Copenhagen University
Proceedings of the Annual ACM-SIAM Symposium on Discrete Algorithms | Year: 2013

Given an undirected graph G with m edges, n vertices, and non-negative edge weights, and given an integer k ≥ 2, we show that a (2k - 1)-approximate distance oracle for G of size O(kn1+1/k) and with O(log k) query time can be constructed in O(min{kmn1/k, √km + kn 1+c/√k}) time for some constant c. This improves the O(k) query time of Thorup and Zwick. Furthermore, for any 0 < ε ≤ 1, we give an oracle of size O(kn1+1/k) that answers ((2 + ε)k)-approximate distance queries in O(1/ε) time. At the cost of a k-factor in size, this improves the 128k approximation achieved by the constant query time oracle of Mendel and Naor and approaches the best possible tradeoff between size and stretch, implied by a widely believed girth conjecture of Erdo{combining double acute accent}s. We can match the O(n1+1/k) size bound of Mendel and Naor for any constant ε > 0 and k = O(log n/ log log n). Copyright © SIAM.


Cinar A.B.,Copenhagen University
Oral health & preventive dentistry | Year: 2011

To assess any clustering between obesity, dental health, and lifestyle factors (dietary patterns, physical activity, smoking, and alcohol consumption) among adolescents. A cluster sample of 15-year-old Danish adolescents (DA) from eight municipalities was selected. Self-reported questionnaires for adolescents and their mothers to assess body-mass index (BMI), socioeconomic and lifestyle factors, and clinical examinations to examine adolescents' dental status (DMFT) were used. Descriptive statistics, chi-square tests, and factor analysis were applied. The mean DMFT was 2.03 and mean BMI was 21.30 among DA.Of the whole sample, 62% experienced caries (DMFT > 0) and 16% were classified as obese. No association appeared between obesity and DMFT (p > 0.05). Most adolescents were likely to have breakfast every day (76%), but their daily consumption of fruit was lower (38%). More than half of adolescents reported having physical exercise (66%) and no alcohol consumption (57%). Smokers were more likely to consume alcohol (80%) but less likely to exercise (44%) than nonsmokers (alcohol consumption, 55%; exercise, 68%), (P < 0.05). Principal component analysis revealed that DMFT and obesity were interrelated in DA. In line with earlier studies, obesity and dental caries share common lifestyle factors among adolescents, regardless of nationality and different health-care systems. Thus, it seems that dental health is a global health concern. There is a need for collaboration between dental and general health-care providers to manage both obesity and dental caries in adolescents by using a holistic approach.


Intervertebral disc calcification and herniation commonly affects Dachshund where the predisposition is caused by an early onset degenerative process resulting in disc calcification. A continuous spectrum of disc degeneration is seen within and among dog breeds, suggesting a multifactorial etiology. The number of calcified discs at 2 years of age determined by a radiographic evaluation is a good indicator of the severity of disc degeneration and thus serves as a measure for the risk of developing intervertebral disc herniation. The aim of the study was to identify genetic variants associated with intervertebral disc calcification in Dachshund through a genome-wide association (GWA) study. Based on thorough radiographic examinations, 48 cases with ≥ 6 disc calcifications or surgically treated for disc herniation and 46 controls with 0-1 disc calcifications were identified. GWA using the Illumina CanineHD BeadChip identified a locus on chromosome 12 from 36.8 to 38.6 Mb with 36 markers reaching genome-wide significance (P(genome) = 0.00001-0.026). This study suggests that a major locus on chromosome 12 harbors genetic variations affecting the development of intervertebral disc calcification in Dachshund.


Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs. It is characterized by chronic progressive degenerative lesions of the mitral valve. The valve leaflets become thickened and prolapse into the left atrium resulting in mitral regurgitation (MR). MMVD is most prevalent in small to medium sized dog breeds, Cavalier King Charles Spaniels (CKCS) in particular. The onset of MMVD is highly age dependent, and at the age of 10 years, nearly all CKCS are affected. The incidence of a similar disease in humans-mitral valve prolapse-is 1-5%. By defining CKCSs with an early onset of MMVD as cases and old dogs with no or mild signs of MMVD as controls, we conducted a genome-wide association study (GWAS) to identify loci associated with development of MMVD. We have identified a 1.58 Mb region on CFA13 (P(genome) = 4.0 × 10(-5)) and a 1.68 Mb region on CFA14 (P(genome) = 7.9 × 10(-4)) associated with development of MMVD. This confirms the power of using the dog as a model to uncover potential candidate regions involved in the molecular mechanisms behind complex traits.


Trott M.,CERN | Trott M.,Copenhagen University
Journal of High Energy Physics | Year: 2015

Abstract: We define “constructed observables” as relating experimental measurements to terms in a Lagrangian while simultaneously making assumptions about possible deviations from the Standard Model (SM), in other Lagrangian terms. Ensuring that the SM effective field theory (EFT) is constrained correctly when using constructed observables requires that their defining conditions are imposed on the EFT in a manner that is consistent with the equations of motion. Failing to do so can result in a “functionally redundant” operator basis (We define the concept of functional redundancy, which is distinct from the usual concept of an operator basis redundancy, in the introduction.) and the wrong expectation as to how experimental quantities are related in the EFT. We illustrate the issues involved considering the S parameter and the off shell triple gauge coupling (TGC) verticies. We show that the relationships between (Formula presented.) decay and the off shell TGC verticies are subject to these subtleties, and how the connections between these observables vanish in the limit of strong bounds due to LEP. The challenge of using constructed observables to consistently constrain the Standard Model EFT is only expected to grow with future LHC data, as more complex processes are studied. © 2015, The Author(s).


Young D.,Copenhagen University
Journal of High Energy Physics | Year: 2012

We consider circular non-BPS Maldacena-Wilson loops in five-dimensional supersymmetric Yang-Mills theory (d = 5 SYM) both as macroscopic strings in the D4-brane geometry and directly in gauge theory. We find that in the Dp-brane geometries for increasing p, p = 4 is the last value for which the radius of the string worldsheet describing the Wilson loop is independent of the UV cut-off. It is also the last value for which the area of the worldsheet can be (at least partially) regularized by the standard Legendre transformation. The asymptotics of the string worldsheet allow the remaining divergence in the regularized area to be determined, and it is found to be logarithmic in the UV cutoff. We also consider the M2-brane in AdS 7 × S 4 which is the M-theory lift of the Wilson loop, and dual to a "Wilson surface" in the (2, 0), d = 6 CFT. We find that it has exactly the same logarithmic divergence in its regularized action. The origin of the divergence has been previously understood in terms of a conformal anomaly for surface observables in the CFT. Turning to the gauge theory, a similar picture is found in d = 5 SYM. The divergence and its coefficient can be recovered by summing the leading divergences in the analytic continuation of dimensional regularization of planar rainbow/ladder diagrams. These diagrams are finite in 5-ε dimensions. The interpretation is that the Wilson loop is renormalized by a factor containing this leading divergence of six-dimensional origin, and also subleading divergences, and that the remaining part of the Wilson loop expectation value is a finite, scheme-dependent quantity. We substantiate this claim by showing that the interacting diagrams at one loop are finite in our regularization scheme in d = 5 dimensions, but not for d ≥ 6. © 2012 SISSA.


Ballin N.Z.,Regional Veterinary and Food Control Authority | Ballin N.Z.,Copenhagen University
Meat Science | Year: 2010

In recent years, interest in meat authenticity has increased. Many consumers are concerned about the meat they eat and accurate labelling is important to inform consumer choice. Authentication methods can be categorised into the areas where fraud is most likely to occur: meat origin, meat substitution, meat processing treatment and non-meat ingredient addition. Within each area the possibilities for fraud can be subcategorised as follows: meat origin-sex, meat cuts, breed, feed intake, slaughter age, wild versus farmed meat, organic versus conventional meat, and geographic origin; meat substitution-meat species, fat, and protein; meat processing treatment-irradiation, fresh versus thawed meat and meat preparation; non-meat ingredient addition-additives and water. Analytical methods used in authentication are as diverse as the authentication problems, and include a diverse range of equipment and techniques. This review is intended to provide an overview of the possible analytical methods available for meat and meat products authentication. In areas where no authentication methods have been published, possible strategies are suggested. © 2010 The American Meat Science Association.


Moller B.L.,Copenhagen University
Current Opinion in Plant Biology | Year: 2010

Cyanogenic glucosides are present in many plants and their ability to liberate toxic HCN offers an immediate chemical defense response to herbivores and pathogens causing damage of the plant tissue. Countermeasures have evolved to overcome this type of defense and in some cases herbivores and pathogens are able to exploit the presence of cyanogenic glucosides to their own advantage. In plants, cyanogenic glucosides have gained additional functionalities as transporters of nitrogen and operation of an endogenous turnover pathway may enable plants to withdraw the nitrogen and glucose deposited in cyanogenic glucosides for use in primary metabolism. The aim of this review is to provide an overview of the new knowledge on these diverse functionalities of cyanogenic glucosides. © 2010 Elsevier Ltd. All rights reserved.


Schmiegelow K.,Copenhagen University
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Second malignant neoplasms (SMNs) after diagnosis of childhood acute lymphoblastic leukemia (ALL) are rare events. We analyzed data on risk factors and outcomes of 642 children with SMNs occurring after treatment for ALL from 18 collaborative study groups between 1980 and 2007. Acute myeloid leukemia (AML; n = 186), myelodysplastic syndrome (MDS; n = 69), and nonmeningioma brain tumor (n = 116) were the most common types of SMNs and had the poorest outcome (5-year survival rate, 18.1% ± 2.9%, 31.1% ± 6.2%, and 18.3% ± 3.8%, respectively). Five-year survival estimates for AML were 11.2% ± 2.9% for 125 patients diagnosed before 2000 and 34.1% ± 6.3% for 61 patients diagnosed after 2000 (P < .001); 5-year survival estimates for MDS were 17.1% ± 6.4% (n = 36) and 48.2% ± 10.6% (n = 33; P = .005). Allogeneic stem-cell transplantation failed to improve outcome of secondary myeloid malignancies after adjusting for waiting time to transplantation. Five-year survival rates were above 90% for patients with meningioma, Hodgkin lymphoma, thyroid carcinoma, basal cell carcinoma, and parotid gland tumor, and 68.5% ± 6.4% for those with non-Hodgkin lymphoma. Eighty-nine percent of patients with brain tumors had received cranial irradiation. Solid tumors were associated with cyclophosphamide exposure, and myeloid malignancy was associated with topoisomerase II inhibitors and starting doses of methotrexate of at least 25 mg/m(2) per week and mercaptopurine of at least 75 mg/m(2) per day. Myeloid malignancies with monosomy 7/5q- were associated with high hyperdiploid ALL karyotypes, whereas 11q23/MLL-rearranged AML or MDS was associated with ALL harboring translocations of t(9;22), t(4;11), t(1;19), and t(12;21) (P = .03). SMNs, except for brain tumors, AML, and MDS, have outcomes similar to their primary counterparts.


Wiegell S.R.,Copenhagen University
Current Problems in Dermatology (Switzerland) | Year: 2015

Photodynamic therapy (PDT) is an attractive treatment option for actinic keratoses (AKs), as large skin areas can be treated with high response rates and superior cosmetic outcome. The efficacy of 5-aminolevulinic acid (ALA)-PDT and methyl aminolevulinate (MAL)-PDT for AK has been proven in multiple studies, and this treatment is recommended in numerous consensus works and therapy guidelines. Moreover, a self-adhesive ALA patch has been approved for the PDT of AK. In a phase III study, ALA-patch-PDT was superior to cryotherapy and placebo in the treatment of mild to moderate AK on the face and scalp, and pre-treatment of the lesions and additional light occlusion was unnecessary when using the patch. ALA with a proprietary nanoemulsion is another newly marketed ALA gel that has been approved for the treatment of mild to moderate AK on the head. ALA was combined with a nanoemulsion to achieve increased chemical stability of the active ingredient and to enhance skin penetration. One study found that ALA was superior to MAL in the treatment of AK on the face or scalp. Daylight-PDT is a simpler and more tolerable treatment procedure for PDT, and three randomised studies have shown that daylight-PDT is an effective and pain-free treatment for AK; however, the procedure is limited by the need for a sufficient light dose and outdoor temperature. Ablative fractional laser resurfacing prior to MAL has been used to improve the PDT response of thick AK. However, more intense acute skin reactions and long-term adverse events in ablative fractional laser resurfacing-PDT compared with PDT-treated skin were found, which might limit the use of the intensified treatment. © 2015 S. Karger AG, Basel.


Zahl P.-H.,Norwegian Institute of Public Health | Gotzsche P.C.,Copenhagen University | Maehlen J.,University of Oslo
The Lancet Oncology | Year: 2011

Background: The natural history of screen-detected breast cancers is not well understood. A previous analysis of the incidence change during the introduction of the Norwegian screening programme in the late 1990s suggested that the natural history of many screen-detected invasive breast cancers is to regress spontaneously but the study was possibly confounded by use of hormone replacement therapy in the population. We did a similar analysis of data collected during an earlier period when few women were exposed to hormone replacement therapy. Methods: We compared cumulative breast cancer incidence in age-matched cohorts of women living in seven Swedish counties before and after the initiation of public mammography screening between 1986 and 1990. Women aged 40-49 years were invited to screening every year and women aged 50-74 years were invited every 2 years. A screened group including all women aged 40-69 years (n=328 927) was followed-up for 6 years after the first invitation to the programme. A control group including all women in the same age range (n=317 404) was also followed-up for 6 years-4 years without screening and 2 years when they entered the screening programme. Screening attendance was much the same in both groups (close to 80%). Counts of incident invasive breast cancers were obtained from the Swedish Cancer Registry (in-situ cancers were excluded). Findings: Before the age-matched controls were invited to be screened at the end of their follow-up period, the 4-year cumulative incidence of invasive breast cancer was significantly higher in the screened group (982 per 100 000) than it was in the control group (658 per 100 000) (relative risk [RR] 1·49, 95% CI 1·41-1·58). Even after prevalence screening in the control group, the screened group had higher 6-year cumulative incidence of invasive breast cancer (1443 per 100 000 vs 1269 per 100 000; RR 1·14, 1·10-1·18). Interpretation: Because the cumulative incidence among controls did not reach that of the screened group, we believe that many invasive breast cancers detected by repeated mammography screening do not persist to be detected by screening at the end of 6 years, suggesting that the natural course of many of the screen-detected invasive breast cancers is to spontaneously regress. Funding: None. © 2011 Elsevier Ltd.


Cells, tissues and organisms have the ability to rapidly switch substrate oxidation from carbohydrate to fat in response to changes in nutrient intake, and to changes in energy demands, environmental cues and internal signals. In healthy, metabolically normal individuals, substrate switching occurs rapidly and completely; in other words, substrate switching is 'flexible'. A growing body of evidence demonstrates that a blunted substrate switching from low- to high-fat oxidation exists in obese individuals, as well as in pre-obese and post-obese, and that this 'metabolic inflexibility' may be a genetically determined trait. A decreased fat oxidation can lead to a positive energy balance under conditions of high-fat feeding, due to depletion of glycogen stores that stimulates appetite and energy intake through glucostatic and glucogenostatic mechanisms, e.g. hepatic sensing of glycogen stores. Several genetic polymorphisms and single-nucleotide polymorphisms have been identified that are associated with low-fat oxidation rates and metabolic inflexibility, and genetic identification of susceptible individuals may lead to personalized prevention of weight gain using fat oxidation stimulants ('fat burners') in the future. © 2011 The Author. obesity reviews © 2011 International Association for the Study of Obesity.


Vallgarda S.,Copenhagen University
Scandinavian journal of public health | Year: 2011

The concept lifestyle disease is used about a number of different diseases such as coronary heart disease, diabetes, lung cancer etc. The concept indicates that people's behaviours cause the diseases. This is only partly true. All diseases, both so-called lifestyle diseases and infectious diseases, have multiple causes. Singling out only one type of causes, such as is implied in the concept of lifestyle diseases can lead prevention to focus only on changing people s behaviours or lifestyles, and thus to neglect other possibilities to improve health. Mortality due to chronic diseases has increased during the last century and the main cause behind this is the decrease in the mortality in infectious diseases among younger people. More people live long enough to develop the chronic diseases. The concept lifestyle disease gives a too narrow picture of causes death and should be abandoned and give place for a broader understanding of causes and preventive options.


Bangalore S.,New York University | Toklu B.,New York University | Wetterslev J.,Copenhagen University
Circulation: Cardiovascular Interventions | Year: 2015

Background - The 2013 American College of Cardiology Foundation/American Heart Association guidelines for patients with ST-segment-elevation myocardial infarction gives a class III indication for nonculprit artery percutaneous coronary intervention at the time of primary percutaneous coronary intervention, driven by data from observational studies. However, more recent trials suggest otherwise. Methods and Results - We conducted PUBMED, EMBASE, and CENTRAL searches for randomized trials comparing complete versus culprit-only revascularization in patients with ST-segment-elevation myocardial infarction. Efficacy outcomes were major adverse cardiovascular events, as well as death, cardiovascular death, myocardial infarction, and repeat revascularization. Safety outcomes were contrast-induced nephropathy, contrast volume used, and procedure time. Five trials with 1165 patients fulfilled the inclusion criteria. Complete revascularization (68% during index percutaneous coronary intervention) was associated with significant reduction in major adverse cardiovascular events (rate ratio =0.48; 95% confidence interval =0.37-0.61), death (rate ratio =0.60; 95% confidence interval =0.38-0.97), cardiovascular death (rate ratio =0.38, 95% confidence interval =0.20-0.73), and repeat revascularization (rate ratio =0.42; 95% confidence interval =0.31-0.57) when compared with culprit-only revascularization. However, trial sequential analyses (similar to interim analysis of a randomized trial) powered for a 25% relative reduction showed firm evidence (cumulative z-curve crossed the monitoring boundary) only for major adverse cardiovascular events driven by a decrease in repeat revascularization with no firm evidence for reduction in death and myocardial infarction. Moreover, there was a significant increase in contrast volume use (mean difference 85.12 [70.41-83.00] ml) and procedure time (mean difference 16.42 [13.22-19.63] mins) with complete revasculariz